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南野 哲男 ミナミノ テツオ

所属
医学部
医学科
職名教授
Last Updated :2020/09/17

研究者基本情報

学歴

  •  - 1996年, 大阪大学
  •  - 1996年, 大阪大学, 医学系研究科
  •  - 1988年, 大阪大学
  •  - 1988年, 大阪大学, 医学部

学位

  • 医学研究科内科系専攻博士, 大阪大学

所属学協会

  • American Journal of Physiology-Heart and Circulatory Physiology
  • 日本循環器学会近畿支部
  • World Journal of Cardiology
  • 国際心臓研究会(ISHR)日本部会
  • 日本内科学会地方会
  • 日本心不全学会
  • 心不全学会
  • 日本内科学会
  • 日本心臓病学会
  • 日本循環器学会
  • The Japanese Society of Internal Medicine
  • The Japanese College of Cardiology
  • Japanese Circulation Society

委員歴

  •   2011年, -: 日本循環器学会近畿支部 評議員
  •   2011年, 日本循環器学会近畿支部, 評議員
  •   2010年, -: American Journal of Physiology-Heart and Circulatory Physiology Editorial Board
  •   2010年, American Journal of Physiology-Heart and Circulatory Physiology, Editorial Board
  •   2009年, -: World Journal of Cardiology Editorila board member
  •   2009年, -: 国際心臓研究会(ISHR)日本部会 評議委員
  •   2009年, World Journal of Cardiology, Editorila board member
  •   2009年, 国際心臓研究会(ISHR)日本部会, 評議委員
  •   2008年, -: 日本心不全学会 評議委員
  •   2008年, -: 日本循環器学会 幹事
  •   2008年, -: 日本循環器学会 第73回日本循環器学会学術集会総会 事務局長
  •   2008年, 日本心不全学会, 評議委員
  •   2008年, 日本循環器学会, 幹事
  •   2008年, 日本循環器学会, 第73回日本循環器学会学術集会総会 事務局長
  •   2007年, -: 日本内科学会地方会 日本内科学会地方会評議委員/近畿支部代表幹事
  •   2007年, 日本内科学会地方会, 日本内科学会地方会評議委員/近畿支部代表幹事

経歴

  •   2002年,  - 2016年, 大阪大学医学部付属病院 循環器内科学, 非常勤医員・助手・外来医長・診療局長・講師・副課長・准教授・病院教授
  •   2016年, - 香川大学医学部循環器腎臓脳卒中内科学, 教授
  •   2004年, -: - Assistant Professor, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine
  •   1999年,  - 2001年, 米国ベイラー医科大学 Schneider MD先生教室, ポスドクフェロー
  •   1998年,  - 2000年, : Research Fellow of the Japan Society for the Promotion of Science for Young Scientists
  •   1998年,  - 1999年, 米国National Jewish Medical and Research Center寺田直弘先生教室, リサーチフェロー
  •   1997年,  - 1998年, 大阪大学医学部病態情報内科学, 研究生
  •   1989年,  - 1992年, : Division of Cardiology, Osaka General Medical Center,
  •   1988年,  - 1989年, 大阪大学医学部附属病院, 研修医

研究活動情報

研究分野

  • ライフサイエンス / 循環器内科学

研究キーワード

    循環器内科, Ubiqutin-proteasome, ER stress, atrial fibrillation, heart failure, myocardial ischemia-reperfusion injury, DDS, nanotechnology

論文

  • Body Fat Area as a Predictive Marker of New-Onset Diabetes Mellitus After Kidney Transplantation., Rikiya Taoka, Kenichi Tanaka, Tadashi Sofue, Yohei Abe, Hirohito Naito, Yasuyuki Miyauchi, Yuki Matsuoka, Motofumi Tajima, Takuma Kato, Hiroyuki Tsunemori, Nobufumi Ueda, Yoshihiro Nishiyama, Tetsuo Minamino, Mikio Sugimoto, Yoshiyuki Kakehi, Transplantation proceedings, Transplantation proceedings, 51, (10) 3281 - 3285,   2019年12月, [査読有り]
  • Development of a Novel Algorithm to Detect Atrial Fibrillation Using an Automated Blood Pressure Monitor With an Irregular Heartbeat Detector., Makoto Ishizawa, Takahisa Noma, Takahiro Izumi, Ryosuke Tani, Tomoko Inoue, Eriko Nasu, Atsushi Tobiume, Yusuke Hasui, Shota Yokoyama, Hideyuki Hamaya, Shohei Ishikawa, Keiji Matsunaga, Ryo Kawakami, Kumi Konishi, Yuichi Miyake, Kaori Ishikawa, Teppei Tsuji, Kazushi Murakami, Naoki Nishimoto, Hiroyuki Kitajima, Tetsuo Minamino, Circulation journal : official journal of the Japanese Circulation Society, Circulation journal : official journal of the Japanese Circulation Society, 83, (12) 2428 - 2433,   2019年11月25日, [査読有り]
  • Anticoagulant therapy and TEVAR in a patient with antiphospholipid syndrome presenting with pulmonary embolisms and multiple arterial embolisms due to thoracic aortic mural thrombosis ., Tani R, Yamashita Y, Matsunaga K, Toyama W, Mantani K, Noma T, Horii T, Minamino T, Journal of cardiology cases, Journal of cardiology cases, 20, (5) 158 - 160,   2019年11月, [査読有り]
  • A 69-year-old woman with extended negative T wave., Matsunaga K, Noma T, Minamino T, Emergency medicine journal : EMJ, Emergency medicine journal : EMJ,   2019年11月, [査読有り]
  • The effects of a participatory structured group educational program on the development of CKD: a population-based study., Tadashi Sofue, Yuka Okano, Nao Matsushita, Masahiro Moritoki, Yoko Nishijima, Hiroshi Fujioka, Yasushi Yamasaki, Masahito Yamanaka, Akira Nishiyama, Tetsuo Minamino, Clinical and experimental nephrology, Clinical and experimental nephrology, 23, (8) 1031 - 1038,   2019年08月, [査読有り]
  • AST-120, an Adsorbent of Uremic Toxins, Improves the Pathophysiology of Heart Failure in Conscious Dogs., Hiroshi Asanuma, Hyemoon Chung, Shin Ito, Kyung-Duk Min, Madoka Ihara, Hiroko Takahama, Marina Funayama, Miki Imazu, Hiroki Fukuda, Akiko Ogai, Yoshihiro Asano, Tetsuo Minamino, Seiji Takashima, Toshisuke Morita, Masaru Sugimachi, Masanori Asakura, Masafumi Kitakaze, Cardiovascular drugs and therapy, Cardiovascular drugs and therapy, 33, (3) 277 - 286,   2019年06月, [査読有り]
  • Early Hyperoxia in The Intensive Care Unit is Significantly Associated With Unfavorable Neurological Outcomes in Patients With Mild-to-Moderate Aneurysmal Subarachnoid Hemorrhage., Shota Yokoyama, Toru Hifumi, Kenya Kawakita, Takashi Tamiya, Tetsuo Minamino, Yasuhiro Kuroda, Shock (Augusta, Ga.), Shock (Augusta, Ga.), 51, (5) 593 - 598,   2019年05月, [査読有り]
  • Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation, Noriaki Yamada, Yoshihiro Asano, Masashi Fujita, Satoru Yamazaki, Atsushi Inanobe, Norio Matsuura, Hatasu Kobayashi, Seiko Ohno, Yusuke Ebana, Osamu Tsukamoto, Saki Ishino, Ayako Takuwa, Hidetaka Kioka, Toru Yamashita, Norio Hashimoto, Dimitar P. Zankov, Akio Shimizu, Masanori Asakura, Hiroshi Asanuma, Hisakazu Kato, Yuya Nishida, Yohei Miyashita, Haruki Shinomiya, Nobu Naiki, Kenshi Hayashi, Takeru Makiyama, Hisakazu Ogita, Katsuyuki Miura, Hirotsugu Ueshima, Issei Komuro, Masakazu Yamagishi, Minoru Horie, Koichi Kawakami, Tetsushi Furukawa, Akio Koizumi, Yoshihisa Kurachi, Yasushi Sakata, Tetsuo Minamino, Masafumi Kitakaze, Seiji Takashima, Circulation, Circulation, 139, (18) 2157 - 2169,   2019年04月, [査読有り]
  • Anti-HB-EGF Antibody-Mediated Delivery of siRNA to Atherosclerotic Lesions in Mice., Shota Tsuchida, Takashi Matsuzaki, Masaki Yamato, Keiji Okuda, Hai Ying Fu, Ryo Araki, Shoji Sanada, Hiroshi Asanuma, Yoshihiro Asano, Masanori Asakura, Hiroyuki Hao, Seiji Takashima, Masafumi Kitakaze, Yasushi Sakata, Eisuke Mekada, Tetsuo Minamino, International heart journal, International heart journal, 59, (6) 1425 - 1431,   2018年11月28日, [査読有り]
  • Development of a novel one-step production system for injectable liposomes under GMP, Ryo Araki, Takashi Matsuzaki, Ayumi Nakamura, Daisaku Nakatani, Shoji Sanada, Hai Ying Fu, Keiji Okuda, Masaki Yamato, Shota Tsuchida, Yasushi Sakata, Tetsuo Minamino, Pharmaceutical Development and Technology, Pharmaceutical Development and Technology, 23, (6) 602 - 607,   2018年07月03日, [査読有り]
  • Post-transplant immunoglobulin A deposition and nephropathy in allografts., Sofue T, Suzuki H, Ueda N, Kushida Y, Minamino T, Nephrology (Carlton, Vic.), Nephrology (Carlton, Vic.), 23 Suppl 2,   2018年07月, [査読有り]
  • Systemic Administration of siRNA with Anti-HB-EGF Antibody-Modified Lipid Nanoparticles for the Treatment of Triple-Negative Breast Cancer, Ayaka Okamoto, Tomohiro Asai, Yusuke Hirai, Kosuke Shimizu, Hiroyuki Koide, Tetsuo Minamino, Naoto Oku, Molecular Pharmaceutics, Molecular Pharmaceutics, 15, (4) 1495 - 1504,   2018年04月02日, [査読有り]
  • Tubular Cell Senescence in the Donated Kidney Predicts Allograft Function, but Not Donor Remnant Kidney Function, in Living Donor Kidney Transplantation., Tadashi Sofue, Yoshio Kushida, Taro Ozaki, Masahiro Moritoki, Yoko Nishijima, Hiroyuki Ohsaki, Nobufumi Ueda, Yoshiyuki Kakehi, Akira Nishiyama, Tetsuo Minamino, American journal of nephrology, American journal of nephrology, 47, (1) 8 - 17,   2018年, [査読有り]
  • Low-dose erythropoietin in patients with ST-segment elevation myocardial infarction (EPO-AMI-II): ― A randomized controlled clinical trial ―, Tetsuo Minamino, Shuichiro Higo, Ryo Araki, Shungo Hikoso, Daisaku Nakatani, Hiroshi Suzuki, Takahisa Yamada, Masaaki Okutsu, Kouji Yamamoto, Yasushi Fujio, Yoshio Ishida, Takuya Ozawa, Kiminori Kato, Ken Toba, Yoshifusa Aizawa, Issei Komuro, T. Toba, T. Ishimitsu, S. Higo, Y. Yasumura, T. Yamada, Y. Ueda, M. Nishino, H. Ito, H. Suzuki, A. Namiki, T. Tobaru, K. Ando, S. Yasuda, Y. Doi, S. Koba, M. Yasutake, Y. Akashi, S. Saito, M. Okutsu, Y. Kijima, T. Yoshida, N. Sato, Y. Sakai, Y. Ohira, EPO-AMI-II Investigators, Circulation Journal, Circulation Journal, 82, (4) 1083 - 1091,   2018年, [査読有り]
  • Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice., Ryo Kawakami, Yoichi Nozato, Hironori Nakagami, Yuka Ikeda, Munehisa Shimamura, Shota Yoshida, Jiao Sun, Tomohiro Kawano, Yoichi Takami, Takahisa Noma, Hiromi Rakugi, Tetsuo Minamino, Ryuichi Morishita, PloS one, PloS one, 13,   2018年, [査読有り]
  • Adult aortic coarctation presenting with refractory heart failure and pulsation below the bilateral clavicle, Tomoko Inoue, Keiji Matsunaga, Kaori Ishikawa, Kazushi Murakami, Takahisa Noma, Taiko Horii, Tetsuo Minamino, Journal of Cardiology Cases, Journal of Cardiology Cases, 18, (3) 85 - 87,   2018年, [査読有り]
  • Association of abnormal carbon dioxide levels with poor neurological outcomes in aneurysmal subarachnoid hemorrhage: a retrospective observational study., Shota Yokoyama, Toru Hifumi, Tomoya Okazaki, Takahisa Noma, Kenya Kawakita, Takashi Tamiya, Tetsuo Minamino, Yasuhiro Kuroda, Journal of intensive care, Journal of intensive care, 6,   2018年, [査読有り]
  • Novel Synthesized Radical-Containing Nanoparticles Limit Infarct Size Following Ischemia and Reperfusion in Canine Hearts, Hiroshi Asanuma, Shoji Sanada, Toru Yoshitomi, Hideyuki Sasaki, Hiroyuki Takahama, Madoka Ihara, Hiroko Takahama, Yoshiro Shinozaki, Hidezo Mori, Masanori Asakura, Atsushi Nakano, Masaru Sugimachi, Yoshihiro Asano, Tetsuo Minamino, Seiji Takashima, Yukio Nagasaki, Masafumi Kitakaze, CARDIOVASCULAR DRUGS AND THERAPY, CARDIOVASCULAR DRUGS AND THERAPY, 31, (5-6) 501 - 510,   2017年12月, [査読有り]
  • Apoptosis inhibitor of macrophage depletion decreased M1 macrophage accumulation and the incidence of cardiac rupture after myocardial infarction in mice, Shohei Ishikawa, Takahisa Noma, Hai Ying Fu, Takashi Matsuzaki, Makoto Ishizawa, Kaori Ishikawa, Kazushi Murakami, Naoki Nishimoto, Akira Nishiyama, Tetsuo Minamino, PLOS ONE, PLOS ONE, 12,   2017年11月, [査読有り]
  • Role of the Low-Density Lipoprotein-Cholesterol/ High-Density Lipoprotein-Cholesterol Ratio in Predicting Serial Changes in the Lipid Component of Coronary Plaque, Ryo Kawakami, Ichiro Matsumoto, Motoi Shiomi, Mizuki Kurozumi, Yuichi Miyake, Makoto Ishizawa, Kaori Ishikawa, Kazushi Murakami, Takahisa Noma, Yuichiro Takagi, Naoki Nishimoto, Tetsuo Minamino, CIRCULATION JOURNAL, CIRCULATION JOURNAL, 81, (10) 1439 - +,   2017年10月, [査読有り]
  • Ablation of IL-33 gene exacerbate myocardial remodeling in mice with heart failure induced by mechanical stress, Punniyakoti T. Veeraveedu, Shoji Sanada, Keiji Okuda, Hai Ying Fu, Takashr Matsuzaki, Ryo Araki, Masaki Yamato, Koubun Yasuda, Yasushi Sakata, Tomohiro Yoshimoto, Tetsuo Minamino, BIOCHEMICAL PHARMACOLOGY, BIOCHEMICAL PHARMACOLOGY, 138,   2017年08月, [査読有り]
  • Protein Quality Control Dysfunction in Cardiovascular Complications Induced by Anti-Cancer Drugs, Hai Ying Fu, Mikio Mukai, Nobuhisa Awata, Yasushi Sakata, Masatsugu Hori, Tetsuo Minamino, CARDIOVASCULAR DRUGS AND THERAPY, CARDIOVASCULAR DRUGS AND THERAPY, 31, (1) 109 - 117,   2017年02月, [査読有り]
  • Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition, Jing Ma, Tao Luo, Zhi Zeng, Haiying Fu, Yoshihiro Asano, Yulin Liao, Tetsuo Minamino, Masafumi Kitakaze, SCIENTIFIC REPORTS, SCIENTIFIC REPORTS, 6,   2016年09月, [査読有り]
  • Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats, Keiji Okuda, Hai Ying Fu, Takashi Matsuzaki, Ryo Araki, Shota Tsuchida, Punniyakoti V. Thanikachalam, Tatsuya Fukuta, Tomohiro Asai, Masaki Yamato, Shoji Sanada, Hiroshi Asanuma, Yoshihiro Asano, Masanori Asakura, Haruo Hanawa, Hiroyuki Hao, Naoto Oku, Seiji Takashima, Masafumi Kitakaze, Yasushi Sakata, Tetsuo Minamino, PLOS ONE, PLOS ONE, 11,   2016年08月, [査読有り]
  • Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy, Shin Ito, Masanori Asakura, Yulin Liao, Kyung-Duk Min, Ayako Takahashi, Kazuhiro Shindo, Satoru Yamazaki, Osamu Tsukamoto, Hiroshi Asanuma, Masaki Mogi, Masatsugu Horiuchi, Yoshihiro Asano, Shoji Sanada, Tetsuo Minamino, Seiji Takashima, Naoki Mochizuki, Masafumi Kitakaze, JOURNAL OF THE AMERICAN HEART ASSOCIATION, JOURNAL OF THE AMERICAN HEART ASSOCIATION, 5,   2016年07月, [査読有り]
  • Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA, Yuki Masumura, Shuichiro Higo, Yoshihiro Asano, Hisakazu Kato, Yi Yan, Saki Ishino, Osamu Tsukamoto, Hidetaka Kioka, Takaharu Hayashi, Yasunori Shintani, Satoru Yamazaki, Tetsuo Minamino, Masafumi Kitakaze, Issei Komuro, Seiji Takashima, Yasushi Sakata, SCIENTIFIC REPORTS, SCIENTIFIC REPORTS, 6,   2016年06月, [査読有り]
  • Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction, Hai Ying Fu, Shoji Sanada, Takashi Matsuzaki, Yulin Liao, Keiji Okuda, Masaki Yamato, Shota Tsuchida, Ryo Araki, Yoshihiro Asano, Hiroshi Asanuma, Masanori Asakura, Brent A. French, Yasushi Sakata, Masafumi Kitakaze, Tetsuo Minamino, CIRCULATION RESEARCH, CIRCULATION RESEARCH, 118, (5) 798 - 809,   2016年03月, [査読有り]
  • Treatment of stroke with liposomal neuroprotective agents under cerebral ischemia conditions, Tatsuya Fukuta, Takayuki Ishii, Tomohiro Asai, Akihiko Sato, Takashi Kikuchi, Kosuke Shimizu, Tetsuo Minamino, Naoto Oku, EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 97, (Pt A) 1 - 7,   2015年11月, [査読有り]
  • An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury., Ihara M, Asanuma H, Yamazaki S, Kato H, Asano Y, Shinozaki Y, Mori H, Minamino T, Asakura M, Sugimachi M, Mochizuki N, Kitakaze M, American journal of physiology. Heart and circulatory physiology, American journal of physiology. Heart and circulatory physiology, 308, (10) H1287 - 97,   2015年05月, [査読有り]
  • Higd1a is a positive regulator of cytochrome c oxidase, Takaharu Hayashi, Yoshihiro Asano, Yasunori Shintani, Hiroshi Aoyama, Hidetaka Kioka, Osamu Tsukamoto, Masahide Hikita, Kyoko Shinzawa-Itoh, Kazuaki Takafuji, Shuichiro Higo, Hisakazu Kato, Satoru Yamazaki, Ken Matsuoka, Atsushi Nakano, Hiroshi Asanuma, Masanori Asakura, Tetsuo Minamino, Yu-ichi Goto, Takashi Ogura, Masafumi Kitakaze, Issei Komuro, Yasushi Sakata, Tomitake Tsukihara, Shinya Yoshikawa, Seiji Takashima, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112, (5) 1553 - 1558,   2015年02月, [査読有り]
  • Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5, Yi Yan, Osamu Tsukamoto, Atsushi Nakano, Hisakazu Kato, Hidetaka Kioka, Noriaki Ito, Shuichiro Higo, Satoru Yamazaki, Yasunori Shintani, Ken Matsuoka, Yulin Liao, Hiroshi Asanuma, Masanori Asakura, Kazuaki Takafuji, Tetsuo Minamino, Yoshihiro Asano, Masafumi Kitakaze, Seiji Takashima, NATURE COMMUNICATIONS, NATURE COMMUNICATIONS, 6,   2015年01月, [査読有り]
  • Carperitide induces coronary vasodilation and limits infarct size in canine ischemic hearts: role of NO, Hiroshi Asanuma, Shoji Sanada, Masanori Asakura, Yoshihiro Asano, Jiyoong Kim, Yoshiro Shinozaki, Hidezo Mori, Tetsuo Minamino, Seiji Takashima, Masafumi Kitakaze, HYPERTENSION RESEARCH, HYPERTENSION RESEARCH, 37, (8) 716 - 723,   2014年08月, [査読有り]
  • Antibody-modified lipid nanoparticles for selective delivery of siRNA to tumors expressing membrane-anchored form of HB-EGF, Ayaka Okamoto, Tomohiro Asai, Hiroki Kato, Hidenori Ando, Tetsuo Minamino, Eisuke Mekada, Naoto Oku, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 449, (4) 460 - 465,   2014年07月, [査読有り]
  • Advanced cancer therapy by integrative antitumor actions via systemic administration of miR-499, Hidenori Ando, Tomohiro Asai, Hiroyuki Koide, Ayaka Okamoto, Noriyuki Maeda, Koji Tomita, Takehisa Dewa, Tetsuo Minamino, Naoto Oku, JOURNAL OF CONTROLLED RELEASE, JOURNAL OF CONTROLLED RELEASE, 181,   2014年05月, [査読有り]
  • Noninvasive and quantitative live imaging reveals a potential stress-responsive enhancer in the failing heart, Ken Matsuoka, Yoshihiro Asano, Shuichiro Higo, Osamu Tsukamoto, Yi Yan, Satoru Yamazaki, Takashi Matsuzaki, Hidetaka Kioka, Hisakazu Kato, Yoshihiro Uno, Masanori Asakura, Hiroshi Asanuma, Tetsuo Minamino, Hiroyuki Aburatani, Masafumi Kitakaze, Issei Komuro, Seiji Takashima, FASEB JOURNAL, FASEB JOURNAL, 28, (4) 1870 - 1879,   2014年04月, [査読有り]
  • Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation, Hidetaka Kioka, Hisakazu Kato, Makoto Fujikawa, Osamu Tsukamoto, Toshiharu Suzuki, Hiromi Imamura, Atsushi Nakano, Shuichiro Higo, Satoru Yamazaki, Takashi Matsuzaki, Kazuaki Takafuji, Hiroshi Asanuma, Masanori Asakura, Tetsuo Minamino, Yasunori Shintani, Masasuke Yoshida, Hiroyuki Noji, Masafumi Kitakaze, Issei Komuro, Yoshihiro Asano, Seiji Takashima, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111, (1) 273 - 278,   2014年01月, [査読有り]
  • Derivation of a mathematical expression for predicting the time to cardiac events in patients with heart failure: a retrospective clinical study, Akemi Yoshida, Masanori Asakura, Hiroshi Asanuma, Akira Ishii, Takuya Hasegawa, Tetsuo Minamino, Seiji Takashima, Hideaki Kanzaki, Takashi Washio, Masafumi Kitakaze, HYPERTENSION RESEARCH, HYPERTENSION RESEARCH, 36, (5) 450 - 456,   2013年05月, [査読有り]
  • Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice, Ayako Takahashi, Masanori Asakura, Shin Ito, Kyung-Duk Min, Kazuhiro Shindo, Yi Yan, Yulin Liao, Satoru Yamazaki, Shoji Sanada, Yoshihiro Asano, Hatsue Ishibashi-Ueda, Seiji Takashima, Tetsuo Minamino, Hiroshi Asanuma, Naoki Mochizuki, Masafumi Kitakaze, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 304, (10) H1361 - H1369,   2013年05月, [査読有り]
  • Treatment of cerebral ischemia-reperfusion injury with PEGylated liposomes encapsulating FK506, Takayuki Ishii, Tomohiro Asai, Dai Oyama, Yurika Agato, Nodoka Yasuda, Tatsuya Fukuta, Kosuke Shimizu, Tetsuo Minamino, Naoto Oku, FASEB JOURNAL, FASEB JOURNAL, 27, (4) 1362 - 1370,   2013年04月, [査読有り]
  • Liposomal Amiodarone augments anti-arrhythmic effects and reduces Hemodynamic adverse effects in an ischemia/ reperfusion rat model, Hiroyuki Takahama, Hirokazu Shigematsu, Tomohiro Asai, Takashi Matsuzaki, Shoji Sanada, Hai Ying Fu, Keiji Okuda, Masaki Yamato, Hiroshi Asanuma, Yoshihiro Asano, Masanori Asakura, Naoto Oku, Issei Komuro, Masafumi Kitakaze, Tetsuo Minamino, Cardiovascular Drugs and Therapy, Cardiovascular Drugs and Therapy, 27, (2) 125 - 132,   2013年04月, [査読有り]
  • Decreased mortality associated with statin treatment in patients with acute myocardial infarction and lymphotoxin-alpha C804A polymorphism, Shinichiro Suna, Yasuhiko Sakata, Daisaku Nakatani, Keiji Okuda, Masahiko Shimizu, Masaya Usami, Sen Matsumoto, Masahiko Hara, Kouichi Ozaki, Hiroya Mizuno, Tetsuo Minamino, Seiji Takashima, Masami Nishino, Yasushi Matsumura, Hiroshi Takeda, Toshihiro Tanaka, Hiroshi Sato, Masatsugu Hori, Issei Komuro, ATHEROSCLEROSIS, ATHEROSCLEROSIS, 227, (2) 373 - 379,   2013年04月, [査読有り]
  • A single injection of liposomal asialo-erythropoietin improves motor function deficit caused by cerebral ischemia/reperfusion, Takayuki Ishii, Tomohiro Asai, Tatsuya Fukuta, Dai Oyama, Nodoka Yasuda, Yurika Agato, Kosuke Shimizu, Tetsuo Minamino, Naoto Oku, INTERNATIONAL JOURNAL OF PHARMACEUTICS, INTERNATIONAL JOURNAL OF PHARMACEUTICS, 439, (1-2) 269 - 274,   2012年12月, [査読有り]
  • Design and Rationale of Low-Dose Erythropoietin in Patients with ST-Segment Elevation Myocardial Infarction (EPO-AMI-II Study): A Randomized Controlled Clinical Trial, Tetsuo Minamino, Ken Toba, Shuichiro Higo, Daisaku Nakatani, Shungo Hikoso, Masao Umegaki, Kouji Yamamoto, Yoshiki Sawa, Yoshifusa Aizawa, Issei Komuro, CARDIOVASCULAR DRUGS AND THERAPY, CARDIOVASCULAR DRUGS AND THERAPY, 26, (5) 409 - 416,   2012年10月, [査読有り]
  • Development of anti-HB-EGF immunoliposomes for the treatment of breast cancer, Kaoru Nishikawa, Tomohiro Asai, Hirokazu Shigematsu, Kosuke Shimizu, Hisakazu Kato, Yoshihiro Asano, Seiji Takashima, Eisuke Mekada, Naoto Oku, Tetsuo Minamino, JOURNAL OF CONTROLLED RELEASE, JOURNAL OF CONTROLLED RELEASE, 160, (2) 274 - 280,   2012年06月, [査読有り]
  • H-2 Mediates Cardioprotection Via Involvements of K-ATP Channels and Permeability Transition Pores of Mitochondria in Dogs, Akemi Yoshida, Hiroshi Asanuma, Hideyuki Sasaki, Shoji Sanada, Satoru Yamazaki, Yoshihiro Asano, Yoshiro Shinozaki, Hidezo Mori, Akito Shimouchi, Motoaki Sano, Masanori Asakura, Tetsuo Minamino, Seiji Takashima, Masaru Sugimachi, Naoki Mochizuki, Masafumi Kitakaze, CARDIOVASCULAR DRUGS AND THERAPY, CARDIOVASCULAR DRUGS AND THERAPY, 26, (3) 217 - 226,   2012年06月, [査読有り]
  • Erythropoietin, progenitor cells and restenosis. A critique of Stein et al., Tetsuo Minamino, Ken Toba, Shuichiro Higo, Daisaku Nakatani, Takuya Ozawa, THROMBOSIS AND HAEMOSTASIS, THROMBOSIS AND HAEMOSTASIS, 107, (6) 1193 - 1193,   2012年06月, [査読有り]
  • Amelioration of cerebral ischemia-reperfusion injury based on liposomal drug delivery system with asialo-erythropoietin, Takayuki Ishii, Tomohiro Asai, Dai Oyama, Tatsuya Fukuta, Nodoka Yasuda, Kosuke Shimizu, Tetsuo Minamino, Naoto Oku, JOURNAL OF CONTROLLED RELEASE, JOURNAL OF CONTROLLED RELEASE, 160, (1) 81 - 87,   2012年05月, [査読有り]
  • Cardioprotection From Ischemia/Reperfusion Injury - Basic and Translational Research, Tetsuo Minamino, CIRCULATION JOURNAL, CIRCULATION JOURNAL, 76, (5) 1074 - 1082,   2012年05月, [査読有り]
  • [The effect of erythropoietin on the improvement of cardiac function in patients with myocardial infarction]., Hikoso S, Minamino T, Komuro I, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 7,   2011年09月, [査読有り]
  • A histamine H₂ receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade., Takahama H, Asanuma H, Sanada S, Fujita M, Sasaki H, Wakeno M, Kim J, Asakura M, Takashima S, Minamino T, Komamura K, Sugimachi M, Kitakaze M, Basic research in cardiology, Basic research in cardiology, 105, (6) 787 - 794,   2010年11月, [査読有り]
  • Endoplasmic Reticulum Stress As a Therapeutic Target in Cardiovascular Disease, Tetsuo Minamino, Issei Komuro, Masafumi Kitakaze, CIRCULATION RESEARCH, CIRCULATION RESEARCH, 107, (9) 1071 - 1082,   2010年10月, [査読有り]
  • ER stress in cardiovascular disease, Tetsuo Minamino, Masafumi Kitakaze, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 48, (6) 1105 - 1110,   2010年06月, [査読有り]
  • Japan Expects Decrements in Both the Incidence and Mortality of Acute Myocardial Infarction in the Modern Era: Likely or Just a Dream?, Masanori Asakura, Tetsuo Minamino, Masafumi Kitakaze, CIRCULATION JOURNAL, CIRCULATION JOURNAL, 74, (1) 43 - 44,   2010年01月, [査読有り]
  • PKA rapidly enhances proteasome assembly and activity in in vivo canine hearts, Mitsutoshi Asai, Osamu Tsukamoto, Tetsuo Minamino, Hiroshi Asanuma, Masashi Fujita, Yoshihiro Asano, Hiroyuki Takahama, Hideyuki Sasaki, Shuichiro Higo, Masanori Asakura, Seiji Takashima, Masatsugu Hori, Masafumi Kitakaze, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 46, (4) 452 - 462,   2009年04月, [査読有り]
  • Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials., Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, Seguchi O, Myoishi M, Minamino T, Ohara T, Nagai Y, Nanto S, Watanabe K, Fukuzawa S, Hirayama A, Nakamura N, Kimura K, Fujii K, Ishihara M, Saito Y, Tomoike H, Kitamura S, J-WIND investigators, Lancet (London, England), Lancet (London, England), 370, (9597) 1483 - 1493,   2007年10月, [査読有り]
  • Impaired glucose tolerance: A possible contributor to left ventricular hypertrophy and diastolic dysfunction, Masashi Fujita, Hiroshi Asanuma, Jiyoong Kim, Yulin Liao, Akio Hirata, Osamu Tsukamoto, Tetsuo Minamino, Masatsugu Hori, Moritaka Goto, Koichi Node, Masafumi Kitakaze, INTERNATIONAL JOURNAL OF CARDIOLOGY, INTERNATIONAL JOURNAL OF CARDIOLOGY, 118, (1) 76 - 80,   2007年05月, [査読有り]
  • New therapeutic application of erythropoietin against ischemic heart diseases, T Minamino, M Kitakaze, JOURNAL OF PHARMACOLOGICAL SCIENCES, JOURNAL OF PHARMACOLOGICAL SCIENCES, 101, (2) 179 - 181,   2006年06月, [査読有り]
  • [Adenosine and ischemic heart disease]., Minamino T, Hori M, Kitakaze M, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 61 Suppl 5,   2003年05月, [査読有り]
  • [Opening of ATP-sensitive potassium channel attenuates cardiac remodeling induced by chronic inhibition of nitric oxide synthesis]., Sanada S, Node K, Asanuma H, Ogita H, Takashima S, Minamino T, Asakura M, Hori M, Kitakaze M, Journal of cardiology, Journal of cardiology, 41, (1) 43 - 44,   2003年01月, [査読有り]
  • Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis - Role of 70-kDa S6 kinase and extracellular signal-regulated kinase, S Sanada, K Node, H Asanuma, H Ogita, S Takashima, T Minamino, M Asakura, WL Liao, A Ogai, J Kim, M Hori, M Kitakaze, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 40, (5) 991 - 997,   2002年09月, [査読有り]

Misc

  • Increase in tumor suppressor Arf compensates gene dysregulation in in vitro aged adipocytes., Hasan AU, 南野哲男他, 18(1), 55-68,   2017年, [査読有り]
  • 第34回心筋代謝研究会YIA ABLATION OF ER STRESS-INITIATED SIGNALING PATHWAY CHOP ATTENUATES CARDIAC DYSFUNCTION BY PRESSURE OVERLOAD-POSSIBLE DOWNSTREANM TARGETS,   2011年
  • シンポジウム<急性心筋梗塞を対象とした臨床試験> 心筋梗塞患者に対するエポエチンベータ投与による心機能改善効果に関する研究-II,   2011年
  • Annual Report of Osaka University -Academic Achievements- 2010-2011 論文100選,   2011年
  • Isoform-specific Intermolecular Disulfide Bond Formation of Heterochromatin Protein 1 (HP1), Shuichiro Higo, Yoshihiro Asano, Hisakazu Kato, Satoru Yamazaki, Atsushi Nakano, Osamu Tsukamoto, Osamu Seguchi, Mitsutoshi Asai, Masanori Asakura, Hiroshi Asanuma, Shoji Sanada, Tetsuo Minamino, Issei Komuro, Masafumi Kitakaze, Seiji Takashima, JOURNAL OF BIOLOGICAL CHEMISTRY, 285, (41), 31337 - 31347,   2010年10月
    Three mammalian isoforms of heterochromatin protein 1 (HP1), alpha, beta, and gamma, play diverse roles in gene regulation. Despite their structural similarity, the diverse functions of these isoforms imply that they are additionally regulated by post-translational modifications. Here, we have identified intermolecular disulfide bond formation of HP1 cysteines in an isoform-specific manner. Cysteine 133 in HP1 alpha and cysteine 177 in HP1 gamma were involved in intermolecular homodimerization. Although both HP1 alpha and HP1 gamma contain reactive cysteine residues, only HP1 gamma readily and reversibly formed disulfide homodimers under oxidative conditions. Oxidatively dimerized HP1 gamma strongly and transiently interacted with TIF1 beta, a universal transcriptional co-repressor. Under oxidative conditions, HP1 gamma dimerized and held TIF1 beta in a chromatin component and inhibited its repression ability. Our results highlight a novel, isoform-specific role for HP1 as a sensor of the cellular redox state.
  • AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation, Atsushi Nakano, Hisakazu Kato, Takashi Watanabe, Kyung-Duk Min, Satoru Yamazaki, Yoshihiro Asano, Osamu Seguchi, Shuichiro Higo, Yasunori Shintani, Hiroshi Asanuma, Masanori Asakura, Tetsuo Minamino, Kozo Kaibuchi, Naoki Mochizuki, Masafumi Kitakaze, Seiji Takashima, NATURE CELL BIOLOGY, 12, (6), 583 - U139,   2010年06月
    AMP-activated protein kinase ( AMPK) is an energy-sensing Ser/Thr protein kinase originally shown to be regulated by AMP(1). AMPK is activated by various cellular stresses that inhibit ATP production or stimulate ATP consumption(2). In addition to its role in metabolism, AMPK has recently been reported to reshape cells by regulating cell polarity and division(3-6). However, the downstream targets of AMPK that participate in these functions have not been fully identified. Here, we show that phosphorylation of the microtubule plus end protein CLIP-170 by AMPK is required for microtubule dynamics and the regulation of directional cell migration. Both inhibition of AMPK and expression of a non-phosphorylatable CLIP-170 mutant resulted in prolonged and enhanced accumulation of CLIP-170 at microtubule tips, and slower tubulin polymerization. Furthermore, inhibition of AMPK impaired microtubule stabilization and perturbed directional cell migration. All of these phenotypes were rescued by expression of a phosphomimetic CLIP-170 mutant. Our results demonstrate, therefore, that AMPK controls basic cellular functions by regulating microtubule dynamics through CLIP-170 phosphorylation.
  • X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes, Tamaki Sawada, Tetsuo Minamino, Hai Ying Fu, Mitsutoshi Asai, Keiji Okuda, Tadashi Isomura, Satoru Yamazaki, Yoshihiro Asano, Ken-ichiro Okada, Osamu Tsukamoto, Shoji Sanada, Hiroshi Asanuma, Masanori Asakura, Seiji Takashima, Masafumi Kitakaze, Issei Komuro, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 48, (6), 1280 - 1289,   2010年06月
    The unfolded protein response (UPR) is triggered to assist protein folding when endoplasmic reticulum (ER) function is impaired. Recent studies demonstrated that ER stress can also induce cell-specific genes. In this study, we examined whether X-box binding protein 1 (XBP1), a major UPR-linked transcriptional factor, regulates the expression of brain natriuretic peptide (BNP) in cardiomyocytes. In samples from failing human hearts, extensive splicing of XBP1 was observed along with increased expression of glucose-regulated protein of 78 kDa (GRP78), a target of spliced XBP1 (sXBP1), suggesting that the UPR was induced in heart failure in humans. Interestingly, quantitative real-time PCR revealed a positive correlation between cardiac expression of GRP78 and BNP, leading us to test the hypothesis that sXBP1 regulates BNP as well as GRP78 in cardiomyocytes. A pharmacological ER stressor caused a dose-dependent increase in the expression of sXBP1 and BNP by cultured cardiomyocytes. Short interfering RNA targeting XBP1 suppressed the induction of BNP expression by a pharmacological ER stressor or norepinephrine, which was rescued by the adenovirus-mediated overexpression of sXBP1. The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. Direct binding of sXBP1 to this element was confirmed by the chromatin immunoprecipitation assay. These findings suggest that ER stress observed in failing hearts regulates cardiac BNP expression through a novel promoter region of the AP1/CRE-like element. (C) 2010 Elsevier Ltd. All rights reserved.
  • Identification of genes related to heart failure using global gene expression profiling of human failing myocardium, Kyung-Duk Min, Masanori Asakura, Yulin Liao, Kenji Nakamaru, Hidetoshi Okazaki, Tomoko Takahashi, Kazunori Fujimoto, Shin Ito, Ayako Takahashi, Hiroshi Asanuma, Satoru Yamazaki, Tetsuo Minamino, Shoji Sanada, Osamu Seguchi, Atsushi Nakano, Yosuke Ando, Toshiaki Otsuka, Hidehiko Furukawa, Tadashi Isomura, Seiji Takashima, Naoki Mochizuki, Masafumi Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 393, (1), 55 - 60,   2010年02月
    Although various management methods have been developed for heart failure, it is necessary to investigate the diagnostic or therapeutic targets of heart failure. Accordingly, we have developed different approaches for managing heart failure by using conventional microarray analyses. We analyzed gene expression profiles of myocardial samples from 12 patients with heart failure and constructed datasets of heart failure-associated genes using clinical parameters such as pulmonary artery pressure (PAP) and ejection fraction (EF). From these 12 genes, we selected four genes with high expression levels in the heart, and examined their novelty by performing a literature-based search. In addition, we included four G-protein-coupled receptor (GPCR)-encoding genes, three enzyme-encoding genes, and one ion-channel protein-encoding gene to identify a drug target for heart failure using in silico microarray database. After the in vitro functional screening using adenovirus transfections of 12 genes into rat cardiomyocytes, we generated gene-targeting mice of five candidate genes, namely, MYLA3, GPR37L1, GPR35, MMP23, and NBC1. The results revealed that systolic blood pressure differed significantly between GPR35-KO and GPR35-WT mice as well as between GPR37L1-Tg and GPR37L1-KO mice. Further, the heart weight/body weight ratio between MYLK3-Tg and MYLK3-WT mice and between GPR37L1-Tg and GPR37L1-KO mice differed significantly. Hence, microarray analysis combined with clinical parameters can be an effective method to identify novel therapeutic targets for the prevention or management of heart failure. (C) 2010 Elsevier Inc. All rights reserved.
  • Identification of genes related to heart failure using global gene expression profiling of human failing myocardium, Kyung-Duk Min, Masanori Asakura, Yulin Liao, Kenji Nakamaru, Hidetoshi Okazaki, Tomoko Takahashi, Kazunori Fujimoto, Shin Ito, Ayako Takahashi, Hiroshi Asanuma, Satoru Yamazaki, Tetsuo Minamino, Shoji Sanada, Osamu Seguchi, Atsushi Nakano, Yosuke Ando, Toshiaki Otsuka, Hidehiko Furukawa, Tadashi Isomura, Seiji Takashima, Naoki Mochizuki, Masafumi Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 393, (1), 55 - 60,   2010年02月
    Although various management methods have been developed for heart failure, it is necessary to investigate the diagnostic or therapeutic targets of heart failure. Accordingly, we have developed different approaches for managing heart failure by using conventional microarray analyses. We analyzed gene expression profiles of myocardial samples from 12 patients with heart failure and constructed datasets of heart failure-associated genes using clinical parameters such as pulmonary artery pressure (PAP) and ejection fraction (EF). From these 12 genes, we selected four genes with high expression levels in the heart, and examined their novelty by performing a literature-based search. In addition, we included four G-protein-coupled receptor (GPCR)-encoding genes, three enzyme-encoding genes, and one ion-channel protein-encoding gene to identify a drug target for heart failure using in silico microarray database. After the in vitro functional screening using adenovirus transfections of 12 genes into rat cardiomyocytes, we generated gene-targeting mice of five candidate genes, namely, MYLA3, GPR37L1, GPR35, MMP23, and NBC1. The results revealed that systolic blood pressure differed significantly between GPR35-KO and GPR35-WT mice as well as between GPR37L1-Tg and GPR37L1-KO mice. Further, the heart weight/body weight ratio between MYLK3-Tg and MYLK3-WT mice and between GPR37L1-Tg and GPR37L1-KO mice differed significantly. Hence, microarray analysis combined with clinical parameters can be an effective method to identify novel therapeutic targets for the prevention or management of heart failure. (C) 2010 Elsevier Inc. All rights reserved.
  • 診療に活かす心機能評価 <刺激伝導路系>, 羊土社,   2010年
  • 診療に活かす心機能評価 <冠循環と冠血流調整因子>, 羊土社,   2010年
  • 第33回心筋代謝研究会YIA ER STRESS REGULATES BNP THROUGH A NOVEL AP1/CRE-LIKE ELEMENT IN CARDIOMYOCYTES,   2010年
  • Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload., Circulation,   2010年
  • 最先端・次世代研究開発支援プログラム-ヒアリング,   2010年
  • 第14回日本心不全学会学術集会YIA 小胞体発信アポトーシスシグナルCHOP遺伝子欠失マウスでは圧負荷による心肥大・心不全が抑制される,   2010年
  • Functional alterations of cardiac proteasomes under physiological and pathological conditions, Osamu Tsukamoto, Tetsuo Minamino, Masafumi Kitakaze, CARDIOVASCULAR RESEARCH, 85, (2), 339 - 346,   2010年01月
    The cardiac proteasome is a complex, heterogeneous, and dynamic organelle. Its function is regulated by its molecular organization, post-translational modifications, and associated partner proteins. Pressure overload, ischaemic heart disease, or genetic mutations in contractile proteins can cause heart failure, during which misfolded protein levels are elevated. At the same time, numerous interconnected signal transduction pathways are activated that may modulate any of the three proteasomal regulatory mechanisms mentioned above, resulting in functional changes in cardiac proteasomes. Many lines of evidence support the important role of the ubiquitin-proteasome system (UPS) in the development of heart diseases. Many researchers have focused on the UPS, applying new drug discovery methods not only in the field of cancer research but also in cardiovascular fields such as cardiac hypertrophy and ischaemic heart diseases. More understanding of UPS in the pathophysiology of heart diseases will lead to new routes for therapy.
  • Japan Expects Decrements in Both the Incidence and Mortality of Acute Myocardial Infarction in the Modern Era: Likely or Just a Dream?, Masanori Asakura, Tetsuo Minamino, Masafumi Kitakaze, CIRCULATION JOURNAL, 74, (1), 43 - 44,   2010年01月
  • Functional alterations of cardiac proteasomes under physiological and pathological conditions., Cardiovasc Res, 85(2):339-46,   2010年
  • Natriuretic Peptides Enhance the Production of Adiponectin in Human Adipocytes and in Patients With Chronic Heart Failure, Osamu Tsukamoto, Masashi Fujita, Mahoto Kato, Satoru Yamazaki, Yoshihiro Asano, Akiko Ogai, Hidetoshi Okazaki, Mitsutoshi Asai, Yoko Nagamachi, Norikazu Maeda, Yasunori Shintani, Tetsuo Minamino, Masanori Asakura, Ichiro Kishimoto, Tohru Funahashi, Hitonobu Tomoike, Masafumi Kitakaze, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 53, (22), 2070 - 2077,   2009年06月
    Objectives We investigated the functional relationship between natriuretic peptides and adiponectin by performing both experimental and clinical studies. Background Natriuretic peptides are promising candidates for the treatment of congestive heart failure (CHF) because of their wide range of beneficial effects on the cardiovascular system. Adiponectin is a cytokine derived from adipose tissue with various cardiovascular-protective effects that has been reported to show a positive association with plasma brain natriuretic peptide (BNP) levels in patients with heart failure. Methods The expression of adiponectin messenger ribonucleic acid (mRNA) and its secretion were examined after atrial natriuretic peptide (ANP) or BNP was added to primary cultures of human adipocytes in the presence or absence of HS142-1 (a functional type A guanylyl cyclase receptor antagonist). Changes of the plasma adiponectin level were determined in 30 patients with CHF who were randomized to receive intravenous ANP (0.025 mu g/kg/min human ANP for 3 days, n = 15) or saline (n = 15). Results Both ANP and BNP dose-dependently enhanced the expression of adiponectin mRNA and its secretion, whereas such enhancement was inhibited by pre-treatment with HS142-1. The plasma adiponectin level was increased at 4 days after administration of human ANP compared with the baseline value (from 6.56 +/- 0.40 mu g/ml to 7.34 +/- 0.47 mu g/ml, p < 0.05), whereas there was no change of adiponectin in the saline group (from 6.53 +/- 0.57 mu g/ml to 6.55 +/- 0.56 mu g/ ml). Conclusions Natriuretic peptides enhance adiponectin production by human adipocytes in vitro and even in patients with CHF, which might have a beneficial effect on cardiomyocytes in patients receiving recombinant natriuretic peptide therapy for heart failure. (J Am Coll Cardiol 2009;53:2070-7) (C) 2009 by the American College of Cardiology Foundation
  • Metformin Prevents Progression of Heart Failure in Dogs Role of AMP-Activated Protein Kinase, Hideyuki Sasaki, Hiroshi Asanuma, Masashi Fujita, Hiroyuki Takahama, Masakatsu Wakeno, Shin Ito, Akiko Ogai, Masanori Asakura, Jiyoong Kim, Tetsuo Minamino, Seiji Takashima, Shoji Sanada, Masaru Sugimachi, Kazuo Komamura, Naoki Mochizuki, Masafumi Kitakaze, CIRCULATION, 119, (19), 2568 - U74,   2009年05月
    Background-Some studies have shown that metformin activates AMP-activated protein kinase (AMPK) and has a potent cardioprotective effect against ischemia/reperfusion injury. Because AMPK also is activated in animal models of heart failure, we investigated whether metformin decreases cardiomyocyte apoptosis and attenuates the progression of heart failure in dogs. Methods and Results-Treatment with metformin (10 mu mol/L) protected cultured cardiomyocytes from cell death during exposure to H(2)O(2) (50 mu mol/L) via AMPK activation, as shown by the MTT assay, terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling staining, and flow cytometry. Continuous rapid ventricular pacing (230 bpm for 4 weeks) caused typical heart failure in dogs. Both left ventricular fractional shortening and left ventricular end-diastolic pressure were significantly improved in dogs treated with oral metformin at 100 mg . kg(-1) . d(-1) (n=8) (18.6 +/- 1.8% and 11.8 +/- 1.1 mm Hg, respectively) compared with dogs receiving vehicle (n=8) (9.6 +/- 0.7% and 22 +/- 0.9 mm Hg, respectively). Metformin also promoted phosphorylation of both AMPK and endothelial nitric oxide synthase, increased plasma nitric oxide levels, and improved insulin resistance. As a result of these effects, metformin decreased apoptosis and improved cardiac function in failing canine hearts. Interestingly, another AMPK activator (AICAR) had effects equivalent to those of metformin, suggesting the primary role of AMPK activation in reducing apoptosis and preventing heart failure. Conclusions-Metformin attenuated oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with activation of AMPK. Therefore, metformin may be a potential new therapy for heart failure. (Circulation. 2009; 119: 2568-2577.)
  • Prolonged Targeting of Ischemic/Reperfused Myocardium by Liposomal Adenosine Augments Cardioprotection in Rats, Hiroyuki Takahama, Tetsuo Minamino, Hiroshi Asanuma, Masashi Fujita, Tomohiro Asai, Masakatsu Wakeno, Hideyuki Sasaki, Hiroshi Kikuchi, Kouichi Hashimoto, Naoto Oku, Masanori Asakura, Jiyoong Kim, Seiji Takashima, Kazuo Komamura, Masaru Sugimachi, Naoki Mochizuki, Masafumi Kitakaze, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 53, (8), 709 - 717,   2009年02月
    Objectives The purpose of this study was to investigate whether liposomal adenosine has stronger cardioprotective effects and fewer side effects than free adenosine. Background Liposomes are nanoparticles that can deliver various agents to target tissues and delay degradation of these agents. Liposomes coated with polyethylene glycol (PEG) prolong the residence time of drugs in the blood. Although adenosine reduces the myocardial infarct (MI) size in clinical trials, it also causes hypotension and bradycardia. Methods We prepared PEGylated liposomal adenosine (mean diameter 134 +/- 21 nm) by the hydration method. In rats, we evaluated the myocardial accumulation of liposomes and MI size at 3 h after 30 min of ischemia followed by reperfusion. Results The electron microscopy and ex vivo bioluminescence imaging showed the specific accumulation of liposomes in ischemic/reperfused myocardium. Investigation of radioisotope-labeled adenosine encapsulated in PEGylated liposomes revealed a prolonged blood residence time. An intravenous infusion of PEGylated liposomal adenosine (450 mu g/kg/min) had a weaker effect on blood pressure and heart rate than the corresponding dose of free adenosine. An intravenous infusion of PEGylated liposomal adenosine (450 mu g/kg/min) for 10 min from 5 min before the onset of reperfusion significantly reduced MI size (29.5 +/- 6.5%) compared with an infusion of saline (53.2 +/- 3.5%, p < 0.05). The antagonist of adenosine A(1), A(2a), A(2b), or A(3) subtype receptor blocked cardioprotection observed in the PEGylated liposomal adenosine-treated group. Conclusions An infusion as PEGylated liposomes augmented the cardioprotective effects of adenosine against ischemia/reperfusion injury and reduced its unfavorable hemodynamic effects. Liposomes are promising for developing new treatments for acute MI. (J Am Coll Cardiol 2009; 53: 709-17) (C) 2009 by the American College of Cardiology Foundation
  • 第59回日本体質医学会総会シンポジウム<体質とcommon disease> 体質と心房細動,   2009年
  • 重症心不全の予防と治療-第1章 重症心不全を理解する-4.心筋代謝の面から, 中外医学社,   2009年
  • 第3回 北陸糖尿病・血管・再生研究会<心筋梗塞治療法の開発・TRの現状>,   2009年
  • ER stress in cardiovascular disease, 2009 Nov 12. [Epub ahead of print],   2009年
  • 座談会:臨床家たちが語るDDSの臨床応用, Drug Delivery System, 2009、Vol 24、1,   2009年
  • Latest Development of Nanotechonology Revolutionizes Treatments of Cardiovascular Diseases,   2009年
  • Ablation of C/EBP Homologous Protein Attenuates ER-mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload, 73rd Annumal Scientific Meeting of The Japanese Circulation Society.Symposium 10 ,   2009年
  • 第88回大阪府立成人病センターセミナーシリーズ ミニシンポジウム<Cancer Therapeutics and Cardiotoxicity> 小胞体ケミカルシャペロンによるドキソルビシン心毒性の軽減効果,   2009年
  • 第25回日本DDS学会<シンポジウム3 DDSの臨床応用> ナノサイズリポソームを用いた急性心筋梗塞治療法の開発,   2009年
  • Ablation of C/EBP Homologous Protein Attenuates ER-mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload, 73rd Annumal Scientific Meeting of The Japanese Circulation Society.Symposium 10 ,   2009年
  • Latest Development of Nanotechonology Revolutionizes Treatments of Cardiovascular Diseases,   2009年
  • Identification of a novel substrate for TNF alpha-induced kinase NUAK2, Hiroyuki Yamamoto, Seiji Takashima, Yasunori Shintani, Satoru Yamazaki, Osamu Seguchi, Atsushi Nakano, Shuichiro Higo, Hisakazu Kato, Yulin Liao, Yoshihiro Asano, Tetsuo Minamino, Yasushi Matsumura, Hiroshi Takeda, Masafumi Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 365, (3), 541 - 547,   2008年01月
    TNF alpha has multiple important cellular functions both in normal cells and in tumor cells. To explore the role of TNF alpha, we identified NUAK family, SNF1-like kinase 2 (NUAK2), as a TNF alpha-induced kinase by gene chip analysis. NUAK2 is known to be induced by various cellular stresses and involved in cell mortality, however, its substrate has never been identified. We developed original protocol of de novo screening for kinase substrates using an in vitro kinase assay and high performance liquid chromatography (HPLC). Using this procedure, we identified myosin phosphatase target subunit 1 (MYPT1) as a specific substrate for NUAK2. MYPT1 was phosphorylated at another site(s) by NUAK2, other than known Rho-kinase phosphorylation sites (Thr696 or Thr853) responsible for inhibition of myosin phosphatase activity. These data suggests different phosphorylation and regulation of MYPT1 activity by NUAK2. (c) 2007 Elsevier Inc. All rights reserved.
  • Atorvastatin slows the progression of cardiac remodeling in mice with pressure overload and inhibits epidermal growth factor receptor activation,   2008年
  • Identification of p32 as a novel substrate for ATM in heart, Biochem Biophys Res Commun, 365(3):541-7,   2008年
  • Nano-size liposome coated with polyethyleneglycol can deliver drugs to ischemia/reperfused myocardiu, 第72回日本循環器学会総会・学術集会・プレナリーセッション<Myocardial Protection Strategy after Reperfusion Therapy in Acute Coronary Syndrome>,   2008年
  • Overexpression of ER-resident Chaperone Attenuates Cardiomyocyte Death Induced by Proteasome Inhibition, Cardiovas Res,   2008年
  • 冠動脈プラーク破綻の新しい指標-小胞体ストレス誘導分子の測定キット開発, 第56回日本心臓病学会学術集会・パネルディスカッション PD-7.「心血管疾患のバイオマーカー」,   2008年
  • ナノサイズリポソームを用いた新しい心筋梗塞治療法の開発,   2008年
  • ナノテクノロジーを用いた新しい心筋梗塞治療法の開発, 第56回日本心臓病学会学術集会・パネルディスカッションパネルディスカッション: PD-2.「急性冠症候群の治療法の進歩」,   2008年
  • 小胞体ストレス誘導分子の心不全マーカーとしての有用性, 第12回日本心不全学会学術大会 シンポジウム:心不全における心筋バイオマーカー,   2008年
  • Inhibition of cardiac remodeling by pravastatin is associated with amelioration of endoplasmic reticulum stress, Hypertens Res,   2008年
  • Overexpression of ER-resident Chaperone Attenuates Cardiomyocyte Death Induced by Proteasome Inhibition, Cardiovas Res,   2008年
  • A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart, Osamu Seguchi, Seiji Takashima, Satoru Yamazaki, Masanori Asakura, Yoshihiro Asano, Yasunori Shintani, Masakatsu Wakeno, Tetsuo Minamino, Hiroya Kondo, Hidehiko Furukawa, Kenji Nakamaru, Asuka Naito, Tomoko Takahashi, Toshiaki Ohtsuka, Koichi Kawakami, Tadashi Isomura, Soichiro Kitamura, Hitonobu Tomoike, Naoki Mochizuki, Masafumi Kitakaze, JOURNAL OF CLINICAL INVESTIGATION, 117, (10), 2812 - 2824,   2007年10月
    Marked sarcomere disorganization is a well-documented characteristic of cardiomyocytes in the failing human myocardium. Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC2v), which is involved in the development of human cardiomyopathy, is an important structural protein that affects physiologic cardiac sarcomere formation and heart development. Integrated cDNA expression analysis of failing human myocardia uncovered a novel protein kinase, cardiac-specific myosin light chain kinase (cardiac-MLCK), which acts on MLC2v. Expression levels of cardiac-MLCK were well correlated with the pulmonary arterial pressure of patients with heart failure. In cultured cardiomyocytes, knockdown of cardiac-MLCK by specific siRNAs decreased MLC2v phosphorylation and impaired epinephrine-induced activation of sarcomere reassembly. To further clarify the physiologic roles of cardiac-MLCK in vivo, we cloned the zebrafish ortholog z-cardiac-MLCK. Knockdown of z-cardiac-MLCK expression using morpholino antisense oligonucleotides resulted in dilated cardiac ventricles and immature sarcomere structures. These results suggest a significant role for cardiac-MLCK in cardiogenesis.
  • A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart, Osamu Seguchi, Seiji Takashima, Satoru Yamazaki, Masanori Asakura, Yoshihiro Asano, Yasunori Shintani, Masakatsu Wakeno, Tetsuo Minamino, Hiroya Kondo, Hidehiko Furukawa, Kenji Nakamaru, Asuka Naito, Tomoko Takahashi, Toshiaki Ohtsuka, Koichi Kawakami, Tadashi Isomura, Soichiro Kitamura, Hitonobu Tomoike, Naoki Mochizuki, Masafumi Kitakaze, JOURNAL OF CLINICAL INVESTIGATION, 117, (10), 2812 - 2824,   2007年10月
    Marked sarcomere disorganization is a well-documented characteristic of cardiomyocytes in the failing human myocardium. Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC2v), which is involved in the development of human cardiomyopathy, is an important structural protein that affects physiologic cardiac sarcomere formation and heart development. Integrated cDNA expression analysis of failing human myocardia uncovered a novel protein kinase, cardiac-specific myosin light chain kinase (cardiac-MLCK), which acts on MLC2v. Expression levels of cardiac-MLCK were well correlated with the pulmonary arterial pressure of patients with heart failure. In cultured cardiomyocytes, knockdown of cardiac-MLCK by specific siRNAs decreased MLC2v phosphorylation and impaired epinephrine-induced activation of sarcomere reassembly. To further clarify the physiologic roles of cardiac-MLCK in vivo, we cloned the zebrafish ortholog z-cardiac-MLCK. Knockdown of z-cardiac-MLCK expression using morpholino antisense oligonucleotides resulted in dilated cardiac ventricles and immature sarcomere structures. These results suggest a significant role for cardiac-MLCK in cardiogenesis.
  • Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome, Masafumi Myoishi, Hiroyuki Hao, Tetsuo Minamino, Kouki Watanabe, Kensaku Nishihira, Kinta Hatakeyama, Yujiro Asada, Ken-ichiro Okada, Hatsue Ishibashi-Ueda, Giulio Gabbiani, Marie-Luce Bochaton-Piallat, Naoki Mochizuki, Masafumi Kitakaze, CIRCULATION, 116, (11), 1226 - 1233,   2007年09月
    Background - The endoplasmic reticulum ( ER) responds to various stresses by upregulation of ER chaperones, but prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains unclear. Methods and Results - Coronary artery segments were obtained at autopsy from 71 patients, and atherectomy specimens were obtained from 40 patients. Smooth muscle cells and macrophages in the fibrous caps of thin-cap atheroma and ruptured plaques, but not in the fibrous caps of thick-cap atheroma and fibrous plaques, showed a marked increase of ER chaperone expression and apoptotic cells. ER chaperones also showed higher expression in atherectomy specimens from patients with unstable angina pectoris than in specimens from those with stable angina. Expression of 7-ketocholesterol was increased in the fibrous caps of thin-cap atheroma compared with thick-cap atheroma. Treatment of cultured coronary artery smooth muscle cells or THP-1 cells with 7-ketocholesterol induced upregulation of ER chaperones and apoptosis, whereas these changes were prevented by antioxidants. We also investigated possible signaling pathways for ER-initiated apoptosis and found that the CHOP ( a transcription factor induced by ER stress)- dependent pathway was activated in unstable plaques. In addition, knockdown of CHOP expression by small interfering RNA decreased ER stress-dependent death of cultured coronary artery smooth muscle cells and THP-1 cells. Conclusions - Increased ER stress occurs in unstable plaques. Our findings suggest that ER stress-induced apoptosis of smooth muscle cells and macrophages may contribute to plaque vulnerability.
  • Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome, Masafumi Myoishi, Hiroyuki Hao, Tetsuo Minamino, Kouki Watanabe, Kensaku Nishihira, Kinta Hatakeyama, Yujiro Asada, Ken-ichiro Okada, Hatsue Ishibashi-Ueda, Giulio Gabbiani, Marie-Luce Bochaton-Piallat, Naoki Mochizuki, Masafumi Kitakaze, CIRCULATION, 116, (11), 1226 - 1233,   2007年09月
    Background - The endoplasmic reticulum ( ER) responds to various stresses by upregulation of ER chaperones, but prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains unclear. Methods and Results - Coronary artery segments were obtained at autopsy from 71 patients, and atherectomy specimens were obtained from 40 patients. Smooth muscle cells and macrophages in the fibrous caps of thin-cap atheroma and ruptured plaques, but not in the fibrous caps of thick-cap atheroma and fibrous plaques, showed a marked increase of ER chaperone expression and apoptotic cells. ER chaperones also showed higher expression in atherectomy specimens from patients with unstable angina pectoris than in specimens from those with stable angina. Expression of 7-ketocholesterol was increased in the fibrous caps of thin-cap atheroma compared with thick-cap atheroma. Treatment of cultured coronary artery smooth muscle cells or THP-1 cells with 7-ketocholesterol induced upregulation of ER chaperones and apoptosis, whereas these changes were prevented by antioxidants. We also investigated possible signaling pathways for ER-initiated apoptosis and found that the CHOP ( a transcription factor induced by ER stress)- dependent pathway was activated in unstable plaques. In addition, knockdown of CHOP expression by small interfering RNA decreased ER stress-dependent death of cultured coronary artery smooth muscle cells and THP-1 cells. Conclusions - Increased ER stress occurs in unstable plaques. Our findings suggest that ER stress-induced apoptosis of smooth muscle cells and macrophages may contribute to plaque vulnerability.
  • S-nitrosylated and pegylated hemoglobin, a newly developed artificial oxygen carrier, exerts cardioprotection against ischemic hearts, Hiroshi Asanuma, Kunihiko Nakai, Shoji Sanada, Tetsuo Minamino, Seiji Takashima, Hisakazu Ogita, Masashi Fujita, Akio Hirata, Masakatsu Wakeno, Hiroyuki Takahama, Jiyoong Kim, Masanori Asakura, Ichiro Sakuma, Akira Kitabatake, Masatsugu Hori, Kazuo Komamura, Masafumi Kitakaze, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 42, (5), 924 - 930,   2007年05月
    Cell-free hemoglobin (Hb) derivatives that have been developed as Hb-based artificial oxygen carrier cause both coronary vasoconstriction and platelet aggregation due to the scavenging actions of nitric oxide (NO). Recently, native Hb is found to undergo S-nitrosylation, which regulates blood flow, whereas artificial oxygen carriers are lacking of S-nitrosylation. Therefore, S-nitrosylated and pegylated hemoglobin (SNO-PEG-Hb) was prepared to overcome the above defects, where pegylation was included to avoid extravasation and to prolong the circulatory half-live. Since SNO-PEG-Hb possesses SNO property, we tested whether SNO-PEG-Hb increases coronary blood flow (CBF) and improves the severity of myocardial ischemia. In 19 open chest dogs, the left anterior descending coronary artery was perfused with blood from the carotid artery via the bypass tube, and then CBF and coronary perfusion pressure (CPP) were measured. After hemodynamic stabilization, CPP was reduced so that CBF decreased to 33% of the baseline and thereafter CPP was maintained constant. Ten minutes after the onset of coronary hypoperfusion, we infused 10% SNO-PEG-Hb into the coronary artery (2.5 ml/min). SNO-PEG-Hb increased CBF (28.1 +/- 3.3 to 43.3 +/- 3.9 ml/100 g/min, p<0.05), fractional shortening (4.6 +/- 1.2 to 16.6 +/- 2.4%, p < 0.0 1) and lactate extraction ratio (-38.5 +/- 8.6 to 25.5 +/- 1.3%, p < 0.01). Thus, we conclude that SNO-PEG-Hb increases coronary blood flow and improves the contractile and metabolic dysfunction of the ischemic myocardium. SNO-PEG-Hb, a newly developed artificial oxygen carrier, may mediate a cardioprotection in ischemic heart diseases in addition to blood supplementation. (C) 2006 Elsevier Inc. All rights reserved.
  • Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning, Masashi Fujita, Hiroshi Asanuma, Akio Hirata, Masakatsu Wakeno, Hiroyuki Takahama, Hideyuki Sasaki, Jiyoong Kim, Seiji Takashima, Osamu Tsukamoto, Tetsuo Minamino, Yoshiro Shinozaki, Hitonobu Tomoike, Masatsugu Hori, Masafumi Kitakaze, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 292, (4), H2004 - H2008,   2007年04月
    We have previously reported that the prolonged transient acidosis during early reperfusion mediates the cardioprotective effects in canine hearts. Recently, postconditioning has been shown to be one of the novel strategies to mediate cardio-protection. We tested the contribution of the prolonged transient acidosis to the cardioprotection of postconditioning. Open-chest anesthetized dogs subjected to 90-min occlusion of the left anterior descending coronary artery and 6-h reperfusion were divided into four groups: 1) control group; no intervention after reperfusion (n = 6); 2) postconditioning (Postcon) group; four cycles of 1-min reperfusion and 1-min reocclusion (n = 7); 3) Postcon + sodium bicarbonate (NaHCO3) group; four cycles of 1-min reperfusion and 1-min reocclusion with the administration of NaHCO3 (n = 8); and 4) NaHCO3 group; administration of NaHCO3 without postconditioning (n = 6). Infarct size, the area at risk (AAR), collateral blood flow during ischemia, and pH in coronary venous blood were measured. The phosphorylation of Akt and extracellular signal-regulated kinase (ERK) in ischemic myocardium was assessed by Western blot analysis. Systemic hemodynamic parameters, AAR, and collateral blood flow were not different among the four groups. Postconditioning induced prolonged transient acidosis during the early reperfusion phase. Administration of NaHCO3 completely abolished the infarct size-limiting effects of postconditioning. Furthermore, the phosphorylation of Akt and ERK in ischemic myocardium induced by postconditioning was also blunted by the cotreatment of NaHCO3. In conclusion, postconditioning mediates its cardioprotective effects possibly via prolonged transient acidosis during the early reperfusion phase with the activation of Akt and ERK.
  • Protecting endothelial function: A novel therapeutic target of ATP-sensitive potassium channel openers, Tetsuo Minamino, Masatsugu Hori, CARDIOVASCULAR RESEARCH, 73, (3), 448 - 449,   2007年02月
  • Statin prevents structural and electrical atrial remodeling in rat hypertensive heart failure induce, 第71回日本循環器学会総会 シンポジウム<Heart Failure and Arrhythmia>,   2007年
  • ナノサイズリポソームを用いた急性心筋梗塞治療法の開発, イノベーション・ジャパン2007-大学見本市,   2007年
  • ナノサイズリポソームを用いた急性心筋梗塞治療法の開発, ナノテクノロジーが拓くイノベーションの世界,   2007年
  • Human Atrial Natriuretic Peptide and Nicorandil as an Adjunct to Reperfusion Therapy for Acute Myocardial Infarction with ST-segment Elevation: the Randomised J-WIND (Japan-Working Groups of Acute Myocardial Infarction for the Reduction of Necrotic Dam・・・, Lancet,   2007年
    Human Atrial Natriuretic Peptide and Nicorandil as an Adjunct to Reperfusion Therapy for Acute Myocardial Infarction with ST-segment Elevation: the Randomised J-WIND (Japan-Working Groups of Acute Myocardial Infarction for the Reduction of Necrotic Damage) Trials
  • Blockade of angiotensin II receptors reduces the expression of receptors for advanced glycation end products in human endothelial cells, Masashi Fujita, Hiroko Okuda, Osamu Tsukamoto, Yoshihiro Asano, Yulin Liao, Akio Hirata, Jiyoong Kim, Takeshi Miyatsuka, Seiji Takashima, Tetsuo Minamino, Hitonobu Tomoike, Masafumi Kitakaze, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 26, (10), E138 - E142,   2006年10月
    Objectives - Receptors for advanced glycation end products (RAGEs) play crucial roles in atherogenesis. Because tumor necrosis factor alpha (TNF alpha) is expressed and upregulates RAGE expression in atherosclerotic lesions, the TNF alpha-RAGE interaction might be involved in the inflammatory process of atherogenesis. On the other hand, an angiotensin II type-1 receptor blocker (ARB), widely used as an antihypertensive drug, has been reported to have also antiatherosclerotic effects. Thus we investigated whether an ARB exerts antiatherosclerotic effects via inhibiting the TNF alpha-RAGE interaction. Methods and Results - Stimulation of human endothelial cells with candesartan as well as olmesartan decreased TNF alpha-induced RAGE expression in both mRNA and protein levels along with the decrease in the activity of nuclear factor kappa B and the expression of inflammatory mediators such as vascular cell adhesion molecule (VCAM)-1. Both candesartan and olmesartan inhibited the binding of nuclear factor kappa B to the RAGE gene promoter. Furthermore, gene silencing of RAGE by RNA interference decreased the expression of TNF alpha-induced VCAM-1 in both mRNA and protein levels. Conclusions - RAGE contributes at least partially to the TNF alpha-induced VCAM-1 expression in both mRNA and protein levels. Blockade of angiotensin II receptors might exert antiatherosclerotic effects via reducing TNF alpha-RAGE interaction.
  • Long-term stimulation of adenosine A2b receptors begun after myocardial infarction prevents cardiac remodeling in rats, Masakatsu Wakeno, Tetsuo Minamino, Osamu Seguchi, Hidetoshi Okazaki, Osamu Tsukamoto, Ken-ichiro Okada, Akio Hirata, Masashi Fujita, Hiroshi Asanuma, Jiyoong Kim, Kazuo Komamura, Seiji Takashima, Naoki Mochizuki, Masafumi Kitakaze, CIRCULATION, 114, (18), 1923 - 1932,   2006年10月
    Background - Adenosine inhibits proliferation of cardiac fibroblasts and hypertrophy of cardiomyocytes, both of which may play crucial roles in cardiac remodeling. In the present study, we investigated whether chronic stimulation of adenosine receptors begun after myocardial infarction ( MI) prevents cardiac remodeling. Methods and Results - MI was produced in Wistar rats by permanent ligation of the left anterior descending coronary artery. One week after the onset of MI, animals were randomized into 8 groups: vehicle, dipyridamole ( DIP; the adenosine uptake inhibitor, 50 mg/kg), 2-chroloadenosine ( CADO; the stable analogue of adenosine, 2 mg/ kg), and CADO in the presence of the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline ( 8-SPT) or the selective antagonist for adenosine A1, A2a, A2b, or A3 receptor. Three weeks after treatment, hemodynamic and echocardiographic parameters in the DIP and CADO groups were significantly improved compared with the vehicle group. These hemodynamic and echocardiographic improvements were blunted by either 8-SPT or the selective adenosine A2b antagonist MRS1754 but not by the selective antagonists for other subtypes of adenosine receptors. The collagen volume fraction was smaller, and gene expression of the molecules associated with cardiac remodeling such as matrix metalloproteinase in noninfarcted areas was reduced in the DIP and CADO groups compared with the vehicle group, both of which were attenuated by either 8-SPT or MRS1754. Conclusions - Long-term stimulation of adenosine A2b receptors begun after MI attenuates cardiac fibrosis in the noninfarcted myocardium and improves cardiac function. Drugs that stimulate adenosine A2b receptors or increase adenosine levels are new candidates for preventing cardiac remodeling after MI.
  • Blockade of angiotensin II receptors reduces the expression of receptors for advanced glycation end products in human endothelial cells, Masashi Fujita, Hiroko Okuda, Osamu Tsukamoto, Yoshihiro Asano, Yulin Liao, Akio Hirata, Jiyoong Kim, Takeshi Miyatsuka, Seiji Takashima, Tetsuo Minamino, Hitonobu Tomoike, Masafumi Kitakaze, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 26, (10), E138 - E142,   2006年10月
    Objectives - Receptors for advanced glycation end products (RAGEs) play crucial roles in atherogenesis. Because tumor necrosis factor alpha (TNF alpha) is expressed and upregulates RAGE expression in atherosclerotic lesions, the TNF alpha-RAGE interaction might be involved in the inflammatory process of atherogenesis. On the other hand, an angiotensin II type-1 receptor blocker (ARB), widely used as an antihypertensive drug, has been reported to have also antiatherosclerotic effects. Thus we investigated whether an ARB exerts antiatherosclerotic effects via inhibiting the TNF alpha-RAGE interaction. Methods and Results - Stimulation of human endothelial cells with candesartan as well as olmesartan decreased TNF alpha-induced RAGE expression in both mRNA and protein levels along with the decrease in the activity of nuclear factor kappa B and the expression of inflammatory mediators such as vascular cell adhesion molecule (VCAM)-1. Both candesartan and olmesartan inhibited the binding of nuclear factor kappa B to the RAGE gene promoter. Furthermore, gene silencing of RAGE by RNA interference decreased the expression of TNF alpha-induced VCAM-1 in both mRNA and protein levels. Conclusions - RAGE contributes at least partially to the TNF alpha-induced VCAM-1 expression in both mRNA and protein levels. Blockade of angiotensin II receptors might exert antiatherosclerotic effects via reducing TNF alpha-RAGE interaction.
  • Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs, A Hirata, T Minammo, H Asanuma, M Fujita, M Wakeno, M Myoishi, O Tsukamoto, K Okada, H Koyama, K Komamura, S Takashima, Y Shinozaki, H Mori, M Shiraga, M Kitakaze, M Hori, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 48, (1), 176 - 184,   2006年07月
    OBJECTIVES We investigated the effects of erythropoietin (EPO) on neovascularization and cardiac function after myocardial infarction (MI). BACKGROUND Erythropoietin exerts antiapoptotic effects and mobilizes endothelial progenitor cells (EPCs). METHODS We intravenously administered EPO (1,000 IU/kg) immediately [EPO(0) group], 6 h [EPO(6h) group], or 1 week [EPO(1wk) group] after the permanent ligation of the coronary artery in dogs. Control animals received saline immediately after the ligation. RESULTS The infarct size 6 h after MI was significantly smaller in the EPO(0) group than in the control group (61.5 +/- 6.0% vs. 22.9 +/- 2.2%). One week after MT, the circulating CD34-positive mononuclear cell numbers in both the EPO(0) and the EPO(6h) groups were significantly higher than in the control group. In the ischemic region, the capillary density and myocardial blood flow 4 weeks after MI was significantly higher in both the EPO(0) and the EPO(6h) groups than in the control group. Four weeks after MI, left ventricular (LV) ejection fraction in the EPO(6h) (48.6 +/- 1.9%) group was significantly higher than that in either the control (41.9 +/- 0.9%) or the EPO(1wk) (42.6 +/- 1.2%) group but significantly lower than that in the EPO(0) group (56.1 +/- 2.3%). The LV end-diastolic pressure 4 weeks after MI in both the EPO(0) and the EPO(6h) groups was significantly lower than either the control or the EPO(1wk) group. Hematologic parameters did not differ among the groups. CONCLUSIONS In addition to its acute infarct size-limiting effect, EPO enhances neovascularization, likely via EPC mobilization, and improves cardiac dysfunction in the chronic phase, although it has time-window limitations.
  • Granulocyte colony-stimulating factor mediates cardioprotection against ischemia/reperfusion injury via phosphatidylinositol-3-kinase/akt pathway in canine hearts, Hiroyuki Takahama, Tetsuo Minamino, Akio Hirata, Akiko Ogai, Hiroshi Asanuma, Masashi Fujita, Masakatsu Wakeno, Osamu Tsukamoto, Ken-ichiro Okada, Kazuo Komamura, Seiji Takashima, Yoshiro Shinozaki, Hidezo Mori, Naoki Mochizuki, Masafumi Kitakaze, CARDIOVASCULAR DRUGS AND THERAPY, 20, (3), 159 - 165,   2006年06月
    Purpose Recent studies suggest that G-CSF prevents cardiac remodeling following myocardial infarction (MI) likely through regeneration of the myocardium and coronary vessels. However, it remains unclear whether G-CSF administered at the onset of reperfusion prevents ischemia/reperfusion injury in the acute phase. We investigated acute effects of G-CSF on myocardial infarct size and the incidence of lethal arrhythmia and evaluated the involvement of the phosphatidylinositol-3 kinase (PI3K) in the in vivo canine models. Methods In open-chest dogs, left anterior descending coronary artery (LAD) was occluded for 90 minutes followed by 6 hours of reperfusion. We intravenously administered G-CSF (0.33 mu/kg/min) for 30 minutes from the onset of reperfusion. Wortmannin, a PI3K inhibitor, was selectively administered into the LAD after the onset of reperfusion. Results G-CSF significantly (p < 0.05) reduced myocardial infarct size (38.7 +/- 4.3% to 15.7 +/- 5.3%) and the incidence of ventricular fibrillation during reperfusion periods (50% to 0%) compared with the control. G-CSF enhanced Akt phospholylation in ischemic canine myocardium. Wortmannin blunted both the infarct size-limiting and anti-arrhythmic effects of G-CSF. G-CSF did not change myeloperoxidase activity, a marker of neutrophil accumulation, in the infarcted myocardium. Conclusions An intravenous administration of G-CSF at the onset of reperfusion attenuates ischemia/reperfusion injury through PI3K/Akt pathway in the in vivo model. G-CSF administration can be a promising candidate for the adjunctive therapy for patients with acute myocardial infarction.
  • Granulocyte colony-stimulating factor mediates cardioprotection against ischemia/reperfusion injury via phosphatidylinositol-3-kinase/akt pathway in canine hearts, Hiroyuki Takahama, Tetsuo Minamino, Akio Hirata, Akiko Ogai, Hiroshi Asanuma, Masashi Fujita, Masakatsu Wakeno, Osamu Tsukamoto, Ken-ichiro Okada, Kazuo Komamura, Seiji Takashima, Yoshiro Shinozaki, Hidezo Mori, Naoki Mochizuki, Masafumi Kitakaze, CARDIOVASCULAR DRUGS AND THERAPY, 20, (3), 159 - 165,   2006年06月
    Purpose Recent studies suggest that G-CSF prevents cardiac remodeling following myocardial infarction (MI) likely through regeneration of the myocardium and coronary vessels. However, it remains unclear whether G-CSF administered at the onset of reperfusion prevents ischemia/reperfusion injury in the acute phase. We investigated acute effects of G-CSF on myocardial infarct size and the incidence of lethal arrhythmia and evaluated the involvement of the phosphatidylinositol-3 kinase (PI3K) in the in vivo canine models. Methods In open-chest dogs, left anterior descending coronary artery (LAD) was occluded for 90 minutes followed by 6 hours of reperfusion. We intravenously administered G-CSF (0.33 mu/kg/min) for 30 minutes from the onset of reperfusion. Wortmannin, a PI3K inhibitor, was selectively administered into the LAD after the onset of reperfusion. Results G-CSF significantly (p < 0.05) reduced myocardial infarct size (38.7 +/- 4.3% to 15.7 +/- 5.3%) and the incidence of ventricular fibrillation during reperfusion periods (50% to 0%) compared with the control. G-CSF enhanced Akt phospholylation in ischemic canine myocardium. Wortmannin blunted both the infarct size-limiting and anti-arrhythmic effects of G-CSF. G-CSF did not change myeloperoxidase activity, a marker of neutrophil accumulation, in the infarcted myocardium. Conclusions An intravenous administration of G-CSF at the onset of reperfusion attenuates ischemia/reperfusion injury through PI3K/Akt pathway in the in vivo model. G-CSF administration can be a promising candidate for the adjunctive therapy for patients with acute myocardial infarction.
  • Control of plasma glucose with alpha-glucosidase inhibitor attenuates oxidative stress and slows the progression of heart failure in mice, YL Liao, S Takashima, H Zhao, Y Asano, Y Shintani, T Minamino, J Kim, M Fujita, M Hori, M Kitakaze, CARDIOVASCULAR RESEARCH, 70, (1), 107 - 116,   2006年04月
    Objective: It has been suggested that reduction in glucose levels contributes to the prolongation of life span of rodents in conjunction with restricted food intake, and hyperglycemia has been confirmed as a risk factor for cardiovascular disease (CVD), raising the possibility that better glycemic control could slow the progression of CVD. This study was designed to determine whether impaired glucose tolerance develops during the progression of cardiac hypertrophy and heart failure, and whether tight glycemic control could reduce the severity of heart failure. Methods: In male C57BL/6 mice, transverse aortic constriction (TAC) was employed to create cardiac hypertrophy and heart failure. The involvement of NADPH in TAC mice and cardiac myocytes in the neonatal rat was investigated. Results: The random-fed plasma glucose concentration was higher in TAC mice, and it was reduced to about 100 mg/dL by voglibose (an alpha-glycosidase inhibitor). Four weeks after TAC, both the heart weight/body weight ratio and the lung weight/body weight ratio were lower in the voglibose group than in the TAC group. Echocardiographic and invasive hemodynamic examination showed improvement of left ventricular function in voglibose-treated mice. Voglibose treatment decreased the myocardial expression of an NADPH oxidase subunit (p47(phox)). Glucose dose-dependently increased both neonatal rat myocyte protein synthesis and the expression of p47(phox) protein, while apocynin (an NADPH oxidase inhibitor) blocked the enhancement of protein synthesis by high glucose. Conclusion: Improvement of glycemic control through voglibose therapy inhibited cardiac remodeling by decreasing myocardial oxidative stress in mice with cardiac pressure overload. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
  • The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats, O Tsukamoto, T Minamino, S Sanada, K Okada, A Hirata, M Fujita, Y Shintani, L Yulin, Y Asano, S Takashima, S Yamasaki, H Tomoike, M Hori, M Kitakaze, CARDIOVASCULAR DRUGS AND THERAPY, 20, (2), 93 - 102,   2006年04月
    Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with N-omega-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of ahlosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME + Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 7 vs. 141 +/- 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 +/- 2 vs. 38 +/- 1%)and E/A ratio (1.7 +/- 0.1 vs. 2.1 +/- 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 +/- 0.6 vs. 13.9 +/- 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 +/- 2%), E/A ratio (2.2 +/- 0.1), and LVEDP (6.2 +/- 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism.
  • Control of plasma glucose with alpha-glucosidase inhibitor attenuates oxidative stress and slows the progression of heart failure in mice, YL Liao, S Takashima, H Zhao, Y Asano, Y Shintani, T Minamino, J Kim, M Fujita, M Hori, M Kitakaze, CARDIOVASCULAR RESEARCH, 70, (1), 107 - 116,   2006年04月
    Objective: It has been suggested that reduction in glucose levels contributes to the prolongation of life span of rodents in conjunction with restricted food intake, and hyperglycemia has been confirmed as a risk factor for cardiovascular disease (CVD), raising the possibility that better glycemic control could slow the progression of CVD. This study was designed to determine whether impaired glucose tolerance develops during the progression of cardiac hypertrophy and heart failure, and whether tight glycemic control could reduce the severity of heart failure. Methods: In male C57BL/6 mice, transverse aortic constriction (TAC) was employed to create cardiac hypertrophy and heart failure. The involvement of NADPH in TAC mice and cardiac myocytes in the neonatal rat was investigated. Results: The random-fed plasma glucose concentration was higher in TAC mice, and it was reduced to about 100 mg/dL by voglibose (an alpha-glycosidase inhibitor). Four weeks after TAC, both the heart weight/body weight ratio and the lung weight/body weight ratio were lower in the voglibose group than in the TAC group. Echocardiographic and invasive hemodynamic examination showed improvement of left ventricular function in voglibose-treated mice. Voglibose treatment decreased the myocardial expression of an NADPH oxidase subunit (p47(phox)). Glucose dose-dependently increased both neonatal rat myocyte protein synthesis and the expression of p47(phox) protein, while apocynin (an NADPH oxidase inhibitor) blocked the enhancement of protein synthesis by high glucose. Conclusion: Improvement of glycemic control through voglibose therapy inhibited cardiac remodeling by decreasing myocardial oxidative stress in mice with cardiac pressure overload. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
  • The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats, O Tsukamoto, T Minamino, S Sanada, K Okada, A Hirata, M Fujita, Y Shintani, L Yulin, Y Asano, S Takashima, S Yamasaki, H Tomoike, M Hori, M Kitakaze, CARDIOVASCULAR DRUGS AND THERAPY, 20, (2), 93 - 102,   2006年04月
    Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with N-omega-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of ahlosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME + Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 7 vs. 141 +/- 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 +/- 2 vs. 38 +/- 1%)and E/A ratio (1.7 +/- 0.1 vs. 2.1 +/- 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 +/- 0.6 vs. 13.9 +/- 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 +/- 2%), E/A ratio (2.2 +/- 0.1), and LVEDP (6.2 +/- 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism.
  • Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice, O Tsukamoto, T Minamino, K Okada, Y Shintani, S Takashima, H Kato, YL Liao, H Okazaki, M Asai, A Hirata, M Fujita, Y Asano, S Yamazaki, H Asanuma, M Hori, M Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 340, (4), 1125 - 1133,   2006年02月
    The ubiquitin-proteasome system contributes to regulation of apoptosis degrading apoptosis-regulatory proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired Ubiquitin-proteasome system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of ubiquitin-proteasome system in such conditions. We found that proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. in Cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation. (c) 2005 Elsevier Inc. All rights reserved.
  • Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice, O Tsukamoto, T Minamino, K Okada, Y Shintani, S Takashima, H Kato, YL Liao, H Okazaki, M Asai, A Hirata, M Fujita, Y Asano, S Yamazaki, H Asanuma, M Hori, M Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 340, (4), 1125 - 1133,   2006年02月
    The ubiquitin-proteasome system contributes to regulation of apoptosis degrading apoptosis-regulatory proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired Ubiquitin-proteasome system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of ubiquitin-proteasome system in such conditions. We found that proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. in Cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation. (c) 2005 Elsevier Inc. All rights reserved.
  • 心房細動治療のパラダイムシフト, 日本脳卒中学会総会・ランチョンセミナー<脳卒中とARB>,   2006年
  • アンジオテンシンII受容体拮抗薬は慢性NO合成阻害による高血圧モデル・・・, 第54回日本心臓病学会学術集会・ パネルディスカッション<心房細動の病態と治療戦略>,   2006年
  • Angiotensin II type 1 receptor blocker prevents atrial structural remodeling in rats with hypertension induced by chronic nitric oxide inhibition, Hypertens Res,   2006年
  • New therapeutic application of erythropoietin against ischemic heart diseases, J Pharmacol Sci,   2006年
  • Angiotensin II type 1 receptor blocker prevents atrial structural remodeling in rats with hypertension induced by chronic nitric oxide inhibition, Hypertens Res,   2006年
  • Blockade of histamine H2 receptors protects the heart against ischemia and reperfusion injury in dogs, J Mol Cell Cardiol,   2006年
  • New therapeutic application of erythropoietin against ischemic heart diseases, J Pharmacol Sci,   2006年
  • A role of opening of mitochondrial ATP-sensitive potassium channels in the infarct size-limiting effect of ischemic preconditioning via activation of protein kinase C in the canine heart, O Tsukamoto, H Asanuma, J Kim, T Minamino, S Takashima, A Ogai, A Hirata, M Fujita, Y Shinozaki, H Mori, H Tomoike, M Hori, M Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 338, (3), 1460 - 1466,   2005年12月
    The opening of mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels triggers or mediates the infarct size (IS)-limiting effect of ischemic preconditioning (IP). Because ecto-5'-nucleotidase related to IP is activated by PKC, we tested whether the opening of mitoK(ATP) channels activates PKC and contributes to either activation of ecto-5'-nucleotidase or IS-limiting effect. In dogs, IP procedure decreased IS and activated ecto-5'-nucleotidase, both of which were mimicked by transient exposure to either cromakalim or diazoxide, and these effects were blunted by either GF109203X (a PKC inhibitor) or 5-hydroxydecanoate (a mitoKATP channel blocker), but not by HMR1098 (a surface sarcolenmal K-ATP channel blocker). Either crornakalim or diazoxide activated both PKC and ecto-5-nucleotidase, which was blunted by either GF109203X or 5-hydroxydecanoate, but not by HMR-1098. We concluded that the opening of mitoK(ATP) channels contributes to either activation of ecto-5'-nucleotidase or the infarct size-limiting effect via activation of PKC in canine hearts. (c) 2005 Elsevier Inc. All rights reserved.
  • A role of opening of mitochondrial ATP-sensitive potassium channels in the infarct size-limiting effect of ischemic preconditioning via activation of protein kinase C in the canine heart, O Tsukamoto, H Asanuma, J Kim, T Minamino, S Takashima, A Ogai, A Hirata, M Fujita, Y Shinozaki, H Mori, H Tomoike, M Hori, M Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 338, (3), 1460 - 1466,   2005年12月
    The opening of mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels triggers or mediates the infarct size (IS)-limiting effect of ischemic preconditioning (IP). Because ecto-5'-nucleotidase related to IP is activated by PKC, we tested whether the opening of mitoK(ATP) channels activates PKC and contributes to either activation of ecto-5'-nucleotidase or IS-limiting effect. In dogs, IP procedure decreased IS and activated ecto-5'-nucleotidase, both of which were mimicked by transient exposure to either cromakalim or diazoxide, and these effects were blunted by either GF109203X (a PKC inhibitor) or 5-hydroxydecanoate (a mitoKATP channel blocker), but not by HMR1098 (a surface sarcolenmal K-ATP channel blocker). Either crornakalim or diazoxide activated both PKC and ecto-5-nucleotidase, which was blunted by either GF109203X or 5-hydroxydecanoate, but not by HMR-1098. We concluded that the opening of mitoK(ATP) channels contributes to either activation of ecto-5'-nucleotidase or the infarct size-limiting effect via activation of PKC in canine hearts. (c) 2005 Elsevier Inc. All rights reserved.
  • A calcium channel blocker amlodipine increases coronary blood flow via both adenosine- and NO-dependent mechanisms in ischemic hearts, H Asanuma, T Minamino, S Sanada, H Ogita, J Kim, M Fujita, A Hirata, O Tsukamoto, A Ogai, K Node, M Hori, H Tomoike, M Kitakaze, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 39, (4), 605 - 614,   2005年10月
    Amlodipine reduces oxidative stress that decreases NO and adenosine release. This study was undertaken to examine whether amlodipine mediates coronary vasodilation and improves myocardial metabolism and contractility in ischemic hearts via either adenosine- or NO-dependent mechanisms. In open-chest dogs, amlodipine (2 mu g kg per min) was infused at the minimum dose that caused maximal coronary vasodilation. The perfusion pressure was reduced in the left anterior descending corlonary artery so that coronary blood flow (CBF) decreased by 50%. Amlodipine increased the difference of the adenosine level (VAD (Ado): 119 +/- 14 to 281 +/- 46 nM) and the nitrate + nitrite level (VAD (NOx): 7.8 +/- 1.3 to 16.1 +/- 1.1 mu M) between coronary venous and coronary arterial blood. and also increased CBF (50 +/- 3 to 69 +/- 6 ml/100 g/min). These changes were partially reversed by either 8-sulfophenyeltheophylline (8SPT) or L-omega-nitro argainine, methyl ester (L-NAME), and were completely blocked by both 8SPT and L-NAME. The reduction of CBF increased VAD (8-iso-prostaglandin F-2 alpha), and this increase was reduced by amlodipine (10.8 +/- 1.1 to 5.0 +/- 0.5 pg/ml). In addition, pretreatment with superoxide dismutase mimicked the coronary effects of amlodipine and blunted the response to amlodipine administration. Amlodipine-induced coronary vasodilation via both adenosine- and NO-dependent mechanisms. Adenosine and NO may interact in ischemic hearts to mediate coronary vasodilation by amlodipine. (c) 2005 Elsevier Ltd. All rights reserved.
  • A calcium channel blocker amlodipine increases coronary blood flow via both adenosine- and NO-dependent mechanisms in ischemic hearts, H Asanuma, T Minamino, S Sanada, H Ogita, J Kim, M Fujita, A Hirata, O Tsukamoto, A Ogai, K Node, M Hori, H Tomoike, M Kitakaze, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 39, (4), 605 - 614,   2005年10月
    Amlodipine reduces oxidative stress that decreases NO and adenosine release. This study was undertaken to examine whether amlodipine mediates coronary vasodilation and improves myocardial metabolism and contractility in ischemic hearts via either adenosine- or NO-dependent mechanisms. In open-chest dogs, amlodipine (2 mu g kg per min) was infused at the minimum dose that caused maximal coronary vasodilation. The perfusion pressure was reduced in the left anterior descending corlonary artery so that coronary blood flow (CBF) decreased by 50%. Amlodipine increased the difference of the adenosine level (VAD (Ado): 119 +/- 14 to 281 +/- 46 nM) and the nitrate + nitrite level (VAD (NOx): 7.8 +/- 1.3 to 16.1 +/- 1.1 mu M) between coronary venous and coronary arterial blood. and also increased CBF (50 +/- 3 to 69 +/- 6 ml/100 g/min). These changes were partially reversed by either 8-sulfophenyeltheophylline (8SPT) or L-omega-nitro argainine, methyl ester (L-NAME), and were completely blocked by both 8SPT and L-NAME. The reduction of CBF increased VAD (8-iso-prostaglandin F-2 alpha), and this increase was reduced by amlodipine (10.8 +/- 1.1 to 5.0 +/- 0.5 pg/ml). In addition, pretreatment with superoxide dismutase mimicked the coronary effects of amlodipine and blunted the response to amlodipine administration. Amlodipine-induced coronary vasodilation via both adenosine- and NO-dependent mechanisms. Adenosine and NO may interact in ischemic hearts to mediate coronary vasodilation by amlodipine. (c) 2005 Elsevier Ltd. All rights reserved.
  • Aldosterone nongenomically worsens ischemia via protein kinase C-dependent pathways in hypoperfused canine hearts, M Fujita, T Minamino, H Asanuma, S Sanada, A Hirata, M Wakeno, M Myoishi, H Okuda, A Ogai, K Okada, O Tsukamoto, H Koyama, M Hori, M Kitakaze, HYPERTENSION, 46, (1), 113 - 117,   2005年07月
    Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors ( MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C ( PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery ( LAD) reduced coronary blood flow ( CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone ( 0.1 nmol/L) rapidly decreased CBF ( 37.4 +/- 3.8 to 19.3 +/- 5.2 mL/100 g/min; P < 0.05), along with decreases in fractional shortening ( FS) ( 8.4 +/- 0.7 to 5.4 +/- 0.4%; P < 0.05) and lactate extraction rate ( LER) ( -31.7 +/- 2.9 to -41.4 +/- 3.7%; P < 0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.
  • Aldosterone nongenomically worsens ischemia via protein kinase C-dependent pathways in hypoperfused canine hearts, M Fujita, T Minamino, H Asanuma, S Sanada, A Hirata, M Wakeno, M Myoishi, H Okuda, A Ogai, K Okada, O Tsukamoto, H Koyama, M Hori, M Kitakaze, HYPERTENSION, 46, (1), 113 - 117,   2005年07月
    Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors ( MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C ( PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery ( LAD) reduced coronary blood flow ( CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone ( 0.1 nmol/L) rapidly decreased CBF ( 37.4 +/- 3.8 to 19.3 +/- 5.2 mL/100 g/min; P < 0.05), along with decreases in fractional shortening ( FS) ( 8.4 +/- 0.7 to 5.4 +/- 0.4%; P < 0.05) and lactate extraction rate ( LER) ( -31.7 +/- 2.9 to -41.4 +/- 3.7%; P < 0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.
  • Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model, Y Li, T Minamino, O Tsukamoto, T Yujiri, Y Shintani, K Okada, Y Nagamachi, M Fujita, A Hirata, S Sanada, H Asanuma, S Takashima, M Hori, GL Johnson, M Kitakaze, CIRCULATION, 111, (13), 1672 - 1678,   2005年04月
    Background - Migration, proliferation, and matrix-degrading protease expression of smooth muscle cells (SMCs) are major features of intimal hyperplasia after vascular injury. Although MEK kinase 1 (MEKK1) has been shown to regulate cell migration and urokinase plasminogen activator (uPA) expression, the precise role of MEKK1 in this process remains unknown. Methods and Results - We triggered a vascular remodeling model by complete ligation of the right common carotid artery in wild-type (WT) and MEKK1-null ( MEKK1(-/-)) mice. The intimal areas 28 days after ligation were significantly decreased in the ligated MEKK1(-/-) arteries compared with WT arteries ( 28 +/- 8 versus 65 +/- 17 mu m(2), P < 0.05). There were no differences in the ratios of proliferating cell nuclear antigen ( PCNA) - positive cells to total cells within the arterial wall between WT and MEKK1(-/-) arteries. Proliferation capacity also did not differ between WT and MEKK1(-/-) cultured aortic smooth muscle cells (AoSMCs). In contrast, the number of intimal PCNA-positive cells 7 days after ligation was significantly smaller in MEKK1(-/-) arteries. Three different migration assays revealed that migration and invasion of MEKK1(-/-) AoSMCs were markedly impaired. Addition of full-length MEKK1 restored the migration capacity of MEKK1(-/-) AoSMCs. The number of MEKK1(-/-) AoSMCs showing lamellipodia formation by epithelial growth factor was significantly smaller compared with those of WT SMCs. Furthermore, uPA expression after ligation was markedly decreased in MEKK1(-/-) arteries. Conclusions - MEKK1 is implicated in vascular remodeling after blood-flow cessation by regulating the migration and uPA expression of SMCs. MEKK1 is a potential target for drug development to prevent vascular remodeling.
  • Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model, Y Li, T Minamino, O Tsukamoto, T Yujiri, Y Shintani, K Okada, Y Nagamachi, M Fujita, A Hirata, S Sanada, H Asanuma, S Takashima, M Hori, GL Johnson, M Kitakaze, CIRCULATION, 111, (13), 1672 - 1678,   2005年04月
    Background - Migration, proliferation, and matrix-degrading protease expression of smooth muscle cells (SMCs) are major features of intimal hyperplasia after vascular injury. Although MEK kinase 1 (MEKK1) has been shown to regulate cell migration and urokinase plasminogen activator (uPA) expression, the precise role of MEKK1 in this process remains unknown. Methods and Results - We triggered a vascular remodeling model by complete ligation of the right common carotid artery in wild-type (WT) and MEKK1-null ( MEKK1(-/-)) mice. The intimal areas 28 days after ligation were significantly decreased in the ligated MEKK1(-/-) arteries compared with WT arteries ( 28 +/- 8 versus 65 +/- 17 mu m(2), P < 0.05). There were no differences in the ratios of proliferating cell nuclear antigen ( PCNA) - positive cells to total cells within the arterial wall between WT and MEKK1(-/-) arteries. Proliferation capacity also did not differ between WT and MEKK1(-/-) cultured aortic smooth muscle cells (AoSMCs). In contrast, the number of intimal PCNA-positive cells 7 days after ligation was significantly smaller in MEKK1(-/-) arteries. Three different migration assays revealed that migration and invasion of MEKK1(-/-) AoSMCs were markedly impaired. Addition of full-length MEKK1 restored the migration capacity of MEKK1(-/-) AoSMCs. The number of MEKK1(-/-) AoSMCs showing lamellipodia formation by epithelial growth factor was significantly smaller compared with those of WT SMCs. Furthermore, uPA expression after ligation was markedly decreased in MEKK1(-/-) arteries. Conclusions - MEKK1 is implicated in vascular remodeling after blood-flow cessation by regulating the migration and uPA expression of SMCs. MEKK1 is a potential target for drug development to prevent vascular remodeling.
  • Benidipine, a long-acting calcium channel blocker, inhibits cardiac remodeling in pressure-overloaded mice, YL Liao, M Asakura, S Takashima, A Ogai, Y Asano, H Asanuma, T Minamino, H Tomoike, M Hori, M Kitakaze, CARDIOVASCULAR RESEARCH, 65, (4), 879 - 888,   2005年03月
    Objective: The effects of long-acting calcium channel blockers (CCBs) on pressure overload-induced cardiac remodeling are seldom studied in animals. We evaluated the effects of benidipine, a long-acting CCB, on cardiac remodeling. Methods: Rat neonatal cardiac myocytes were used to examine the influence of benidipine on protein synthesis. Cardiac remodeling was induced in C5 7 B6/J mice by transverse aortic constriction (TAC). Then the effects of benidipine (10 mg/kg/d) were assessed on myocardial hypertrophy and heart failure, cardiac histology, and gene expression. Results: Benidipine significantly inhibited protein synthesis by cardiac myocytes stimulated with phenylephrine (PE), and this effect was partially abolished by cotreatment with a nitric oxide synthase (NOS) inhibitor [N(G)-nitro-L-arginine methylester (L-NAME)]. Four weeks after the onset of pressure overload, benidipine therapy potently inhibited cardiac hypertrophy and prevented heart failure. The heart to body weight ratio was 6.89 +/- 0.48 mg/g in treated mice vs. 8.76 +/- 0.33 mg/g in untreated mice (P<0.01), and the lung to body weight ratio was 7.39 +/- 0.93 mg/g vs. 10.53 +/- 0.99 mg/g, respectively (P<0.05). Left ventricular fractional shortening (LVFS) was improved on echocardiography. Plasma NO levels were increased, while B type natriuretic peptide, protein inhibitor of neuronal NOS, and procollagen IV alpha were down-regulated in benidipine-treated mice. Conclusion: These results indicate that benidipine inhibits cardiac remodeling due to pressure overload at least partly by acting on the nitric oxide signaling pathway. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
  • Benidipine, a long-acting calcium channel blocker, inhibits cardiac remodeling in pressure-overloaded mice, YL Liao, M Asakura, S Takashima, A Ogai, Y Asano, H Asanuma, T Minamino, H Tomoike, M Hori, M Kitakaze, CARDIOVASCULAR RESEARCH, 65, (4), 879 - 888,   2005年03月
    Objective: The effects of long-acting calcium channel blockers (CCBs) on pressure overload-induced cardiac remodeling are seldom studied in animals. We evaluated the effects of benidipine, a long-acting CCB, on cardiac remodeling. Methods: Rat neonatal cardiac myocytes were used to examine the influence of benidipine on protein synthesis. Cardiac remodeling was induced in C5 7 B6/J mice by transverse aortic constriction (TAC). Then the effects of benidipine (10 mg/kg/d) were assessed on myocardial hypertrophy and heart failure, cardiac histology, and gene expression. Results: Benidipine significantly inhibited protein synthesis by cardiac myocytes stimulated with phenylephrine (PE), and this effect was partially abolished by cotreatment with a nitric oxide synthase (NOS) inhibitor [N(G)-nitro-L-arginine methylester (L-NAME)]. Four weeks after the onset of pressure overload, benidipine therapy potently inhibited cardiac hypertrophy and prevented heart failure. The heart to body weight ratio was 6.89 +/- 0.48 mg/g in treated mice vs. 8.76 +/- 0.33 mg/g in untreated mice (P<0.01), and the lung to body weight ratio was 7.39 +/- 0.93 mg/g vs. 10.53 +/- 0.99 mg/g, respectively (P<0.05). Left ventricular fractional shortening (LVFS) was improved on echocardiography. Plasma NO levels were increased, while B type natriuretic peptide, protein inhibitor of neuronal NOS, and procollagen IV alpha were down-regulated in benidipine-treated mice. Conclusion: These results indicate that benidipine inhibits cardiac remodeling due to pressure overload at least partly by acting on the nitric oxide signaling pathway. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
  • Amlodipine ameliorates myocardial hypertrophy by inhibiting EGFR phosphorylation, YL Liao, M Asakura, S Takashima, H Kato, Y Asano, Y Shintani, T Minamino, H Tomoike, M Hori, M Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 327, (4), 1083 - 1087,   2005年02月
    The effects of long-acting calcium channel blockers on pressure overload-induced cardiac hypertrophy have been little studied in experimental animals and the underlying mechanisms are not fully understood. We previously reported that cardiomyocyte hypertrophy could be induced via phosphorylation of the epidermal growth factor receptor (EGFR). In this study, we investigated whether amlodipine attenuates cardiac hypertrophy by inhibiting EGFR phosphorylation. We found that amlodipine dose-dependently inhibited epinephrine-induced protein synthesis and EGFR phosphorylation in cultured neonatal rat cardiomyocytes. Our in vivo study revealed that amlodipine could ameliorate myocardial hypertrophy induced by transverse aortic constriction (TAC) in C57/B6 mice. One week after TAC, amlodipine treatment (3 mg/kg/day) significantly reduced the heart-to-body weight ratio (6.04 +/- 0.16 mg/g vs. 6.90 +/- 0.45 mg/g in untreated TAC mice, P < 0.01). These results indicate that amlodipine ameliorates cardiomyocyte hypertrophy via inhibition of EGFR phosphorylation. (C) 2004 Elsevier Inc. All rights reserved.
  • Amlodipine ameliorates myocardial hypertrophy by inhibiting EGFR phosphorylation, YL Liao, M Asakura, S Takashima, H Kato, Y Asano, Y Shintani, T Minamino, H Tomoike, M Hori, M Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 327, (4), 1083 - 1087,   2005年02月
    The effects of long-acting calcium channel blockers on pressure overload-induced cardiac hypertrophy have been little studied in experimental animals and the underlying mechanisms are not fully understood. We previously reported that cardiomyocyte hypertrophy could be induced via phosphorylation of the epidermal growth factor receptor (EGFR). In this study, we investigated whether amlodipine attenuates cardiac hypertrophy by inhibiting EGFR phosphorylation. We found that amlodipine dose-dependently inhibited epinephrine-induced protein synthesis and EGFR phosphorylation in cultured neonatal rat cardiomyocytes. Our in vivo study revealed that amlodipine could ameliorate myocardial hypertrophy induced by transverse aortic constriction (TAC) in C57/B6 mice. One week after TAC, amlodipine treatment (3 mg/kg/day) significantly reduced the heart-to-body weight ratio (6.04 +/- 0.16 mg/g vs. 6.90 +/- 0.45 mg/g in untreated TAC mice, P < 0.01). These results indicate that amlodipine ameliorates cardiomyocyte hypertrophy via inhibition of EGFR phosphorylation. (C) 2004 Elsevier Inc. All rights reserved.
  • 日本心臓病学会学術集会・シンポジウム<治療難渋性虚血性心疾患に対する治療アプローチ:PCIから再生治療まで>エリスロポエチンは心筋虚血領域における血管新生を促進し、梗塞後慢性期心機能不全を改善する,   2005年
  • Contribution of ER-initiated apoptosis to progression from hypertensive to failing hearts, 第69回日本循環器学会総会・学術集会/シンポジウム<Hypertension and Organ Damage>,   2005年
  • エリスロポイエチンは血管内皮前駆細胞動員により血管新生を促進し、梗塞後心機能不全を改善する, 第4回日本再生医療学会総会/シンポジウム<再生医療の臨床応用最前線>,   2005年
  • エリスロポエチンは心筋虚血領域における血管新生を促進し、梗塞後慢性期新機能不全を改善する, 第53回日本心臓病学会学術集会/ シンポジウム<治療難渋性虚血性心疾患に対するアプローチ:PCIから再生医療まで>,   2005年
  • Erythropoietin stimulates neovascularization of ischemic myocardium and improves left ventricular dy, 2nd international symposium for cardiac anesthesia/Symposium II: Pre-conditioning vs Post-conditioning,   2005年
  • 心臓リモデリングにおけるユビキチン・プロテアソームシステムの役割, 第28回心筋生検研究会/ワークショップ2<心筋細胞変性・細胞死のメカニズムにおける新たな展開>,   2005年
  • Endoplasmic reticulum-initiated apoptotic signaling mediated by CHOP/GADD153 contributes to developm, The 22nd annual meeting of the Japan section of the International Society of Heart Research Panel discussion: What determines the transition from cardiac hypertrophy to heart failure?,   2005年
  • Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts, A Hirata, T Minamino, H Asanuma, S Sanada, M Fujita, O Tsukamoto, M Wakeno, M Myoishi, K Okada, H Koyama, K Komamura, S Takashima, Y Shinozaki, H Mori, H Tomoike, M Hori, M Kitakaze, CARDIOVASCULAR DRUGS AND THERAPY, 19, (1), 33 - 40,   2005年01月
    Although recent studies suggest that erythropoietin (EPO) may reduce multiple features of the myocardial ischemia/reperfusion injury, the cellular mechanisms and the clinical implications of EPO-induced cardioprotection are still unclear. Thus, in this study, we clarified dose-dependent effects of EPO administered just before reperfusion on infarct size and the incidence of ventricular fibrillation and evaluated the involvement of the phosphatidylinositol-3 (PI3) kinase in the in vivo canine model. The canine left anterior descending coronary artery was occluded for 90 min followed by 6 h of reperfusion. A single intravenous administration of EPO just before reperfusion significantly reduced infarct size ( high dose ( 1,000 IU/kg): 7.7 +/- 1.6%, low dose ( 100 IU/kg): 22.1 +/- 2.4%, control: 40.0 +/- 3.6%) in a dose-dependent manner. Furthermore, the high, but not low, dose of EPO administered as a single injection significantly reduced the incidence of ventricular fibrillation during reperfusion ( high dose: 0%, low dose: 40.0%, control: 50.0%). An intracoronary administration of a PI3 kinase inhibitor, wortmannin, blunted the infarct size-limiting and anti-arrhythmic effects of EPO. Low and high doses of EPO equally induced Akt phosphorylation and decreased the equivalent number of TUNEL-positive cells in the ischemic myocardium of dogs. These effects of EPO were abolished by the treatment with wortmannin. In conclusion, EPO administered just before reperfusion reduced infarct size and the incidence of ventricular fibrillation via the PI3 kinase-dependent pathway in canine hearts. EPO administration can be a realistic strategy for the treatment of acute myocardial infarction.
  • Role of endoplasmic reticulum stress in hypertrophic and failing hearts], Nippon Yakurigaku Zasshi,   2005年
  • Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts, A Hirata, T Minamino, H Asanuma, S Sanada, M Fujita, O Tsukamoto, M Wakeno, M Myoishi, K Okada, H Koyama, K Komamura, S Takashima, Y Shinozaki, H Mori, H Tomoike, M Hori, M Kitakaze, CARDIOVASCULAR DRUGS AND THERAPY, 19, (1), 33 - 40,   2005年01月
    Although recent studies suggest that erythropoietin (EPO) may reduce multiple features of the myocardial ischemia/reperfusion injury, the cellular mechanisms and the clinical implications of EPO-induced cardioprotection are still unclear. Thus, in this study, we clarified dose-dependent effects of EPO administered just before reperfusion on infarct size and the incidence of ventricular fibrillation and evaluated the involvement of the phosphatidylinositol-3 (PI3) kinase in the in vivo canine model. The canine left anterior descending coronary artery was occluded for 90 min followed by 6 h of reperfusion. A single intravenous administration of EPO just before reperfusion significantly reduced infarct size ( high dose ( 1,000 IU/kg): 7.7 +/- 1.6%, low dose ( 100 IU/kg): 22.1 +/- 2.4%, control: 40.0 +/- 3.6%) in a dose-dependent manner. Furthermore, the high, but not low, dose of EPO administered as a single injection significantly reduced the incidence of ventricular fibrillation during reperfusion ( high dose: 0%, low dose: 40.0%, control: 50.0%). An intracoronary administration of a PI3 kinase inhibitor, wortmannin, blunted the infarct size-limiting and anti-arrhythmic effects of EPO. Low and high doses of EPO equally induced Akt phosphorylation and decreased the equivalent number of TUNEL-positive cells in the ischemic myocardium of dogs. These effects of EPO were abolished by the treatment with wortmannin. In conclusion, EPO administered just before reperfusion reduced infarct size and the incidence of ventricular fibrillation via the PI3 kinase-dependent pathway in canine hearts. EPO administration can be a realistic strategy for the treatment of acute myocardial infarction.
  • Role of endoplasmic reticulum stress in hypertrophic and failing hearts], Nippon Yakurigaku Zasshi,   2005年
  • Selective blockade of serotonin 5-HT2A receptor increases coronary blood flow via augmented cardiac nitric oxide release through 5-HT1B receptor in hypoperfused canine hearts, M Fujita, T Minamino, S Sanada, H Asanuma, A Hirata, H Ogita, K Okada, O Tsukamoto, S Takashima, H Tomoike, K Node, M Hori, M Kitakaze, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 37, (6), 1219 - 1223,   2004年12月
    Serotonin (5-hydroxytryptamine \5-HT\), which induces vasoconstriction via 5-HT2A receptors in smooth muscle cells and vasodilation through activating nitric oxide (NO) synthase (NOS) via 5-HT1B receptors in endothelial cells, possesses divergent effects on regulating vascular tone. These facts lead LIS to Consider that sarpogrelate, a 5-HT2A receptor blocker, may increase coronary blood flow (CBF) via either attenuation of vasoconstriction through 5-HT2A receptor blockade or augmentation of vasodilation by relative stimulation of NOS through 5-HT1B receptor and we tested this hypothesis in ischemic canine hearts. In open chest dogs, coronary perfusion pressure was reduced so that CBF was decreased to 33% of the baseline and kept constant. Thereafter, sarpogelate was infused selectively into the left anterior descending artery with and without either an inhibitor of NOS (NG-nitro-L-arginine methyl ester (L-NAME)) or a 5-HT1B receptor antagonist (GR55562). An intracoronary administration of sarpogrelate increased CBF (34.0 +/- 4.0 to 44.5 +/- 4.4 ml/100 g/min, P < 0.05). along with the cardiac NOx release (3.2 +/- 0.6 to 6.8 +/- 1.2 nmol/ml, P < 0.05). The increases in both CBF and NOx by sarpogrelate were completely blunted by the co-administration of either L-NAME or GR55562. Interestingly, sarpogrelate increased the cardiac serotonin release (-4.8 +/- 3.2 vs. 22.1 +/- 1.5 ng/ml, P < 0.05, respectively) in the hypoperfused heart. Immunohistochemical analysis showed that sarpogrelate induced serotonin production in ischemic cardiac myocytes. These results Suggest that sarpogrelate increases CBF via augmented cardiac NO production through 5-HT1B receptor activation along with the blockade of 5-HT2A receptors. The increase in cardiac release of serotonin may increase NO production in the ischemic heart. (C) 2004 Elsevier Ltd. All Lights reserved.
  • Optimal windows of statin use for immediate infarct limitation - 5 '-nucleotidase as another downstream molecule of phosphatidylinositol 3-kinase, S Sanada, H Asanuma, T Minamino, K Node, S Takashima, H Okuda, Y Shinozaki, A Ogai, M Fujita, A Hirata, JY Kim, Y Asano, H Mori, H Tomoike, S Kitamura, M Hori, M Kitakaze, CIRCULATION, 110, (15), 2143 - 2149,   2004年10月
    Background-Although statins are reported to have a cardioprotective effect, their immediate direct influence on ischemia-reperfusion injury and the underlying mechanisms remain obscure. We investigated these issues an in vivo canine model. Methods and Results-Dogs were subjected to coronary occlusion (90 minutes) and reperfusion ( 6 hours) immediately after injection of pravastatin (0.2, 2, or 10 mg/kg), pitavastatin (0.01, 0.1, or 0.5 mg/kg), or cerivastatin (0.5, 5, or 50 mug/kg). Then myocardial phosphatidylinositol 3-kinase (PI3-K) and 5'-nucleotidase activities were measured, as well as infarct size. After 15 minutes of reperfusion, pravastatin caused dose-dependent activation of Akt and ecto-5'-nucleotidase in the ischemic zone, and the effect was significant at higher doses. Pitavastatin also significantly increased these activities, and its optimal dose was within the clinical range, whereas cerivastatin caused activation at the lowest dose tested. In all cases, both Akt and ecto-5'-nucleotidase showed activation in parallel, and this activation was completely abolished by wortmannin, a PI3-K inhibitor. The magnitude of the infarct-limiting effect paralleled the increase in Akt and ecto-5'-nucleotidase activity and was blunted by administration of wortmannin, alpha, beta-methyleneadenosine-5'-diphosphate, or 8-sulfophenyltheophylline during reperfusion. Both collateral flow and the area at risk were comparable for all groups. Conclusions-Activation of ecto-5'-nucleotidase after ischemia by PI3-K activation may be crucial for immediate infarct-size limitation by statins. There seems to be an optimal dose for each statin that is independent of its clinical cholesterol-lowering effect.
  • Optimal windows of statin use for immediate infarct limitation - 5 '-nucleotidase as another downstream molecule of phosphatidylinositol 3-kinase, S Sanada, H Asanuma, T Minamino, K Node, S Takashima, H Okuda, Y Shinozaki, A Ogai, M Fujita, A Hirata, JY Kim, Y Asano, H Mori, H Tomoike, S Kitamura, M Hori, M Kitakaze, CIRCULATION, 110, (15), 2143 - 2149,   2004年10月
    Background-Although statins are reported to have a cardioprotective effect, their immediate direct influence on ischemia-reperfusion injury and the underlying mechanisms remain obscure. We investigated these issues an in vivo canine model. Methods and Results-Dogs were subjected to coronary occlusion (90 minutes) and reperfusion ( 6 hours) immediately after injection of pravastatin (0.2, 2, or 10 mg/kg), pitavastatin (0.01, 0.1, or 0.5 mg/kg), or cerivastatin (0.5, 5, or 50 mug/kg). Then myocardial phosphatidylinositol 3-kinase (PI3-K) and 5'-nucleotidase activities were measured, as well as infarct size. After 15 minutes of reperfusion, pravastatin caused dose-dependent activation of Akt and ecto-5'-nucleotidase in the ischemic zone, and the effect was significant at higher doses. Pitavastatin also significantly increased these activities, and its optimal dose was within the clinical range, whereas cerivastatin caused activation at the lowest dose tested. In all cases, both Akt and ecto-5'-nucleotidase showed activation in parallel, and this activation was completely abolished by wortmannin, a PI3-K inhibitor. The magnitude of the infarct-limiting effect paralleled the increase in Akt and ecto-5'-nucleotidase activity and was blunted by administration of wortmannin, alpha, beta-methyleneadenosine-5'-diphosphate, or 8-sulfophenyltheophylline during reperfusion. Both collateral flow and the area at risk were comparable for all groups. Conclusions-Activation of ecto-5'-nucleotidase after ischemia by PI3-K activation may be crucial for immediate infarct-size limitation by statins. There seems to be an optimal dose for each statin that is independent of its clinical cholesterol-lowering effect.
  • Celiprolol, a vasodilatory beta-blocker, inhibits pressure overload-induced cardiac hypertrophy and prevents the transition to heart failure via nitric oxide-dependent mechanisms in mice, YL Liao, M Asakura, S Takashima, A Ogai, Y Asano, Y Shintani, T Minamino, H Asanuma, S Sanada, J Kim, S Kitamura, H Tomoike, M Hori, M Kitakaze, CIRCULATION, 110, (6), 692 - 699,   2004年08月
    Background-The blockade of beta-adrenergic receptors reduces both mortality and morbidity in patients with chronic heart failure, but the cellular mechanism remains unclear. Celiprolol, a selective beta(1)-blocker, was reported to stimulate the expression of endothelial NO synthase (eNOS) in the heart, and NO levels have been demonstrated to be related to myocardial hypertrophy and heart failure. Thus, we aimed to clarify whether celiprolol attenuates both myocardial hypertrophy and heart failure via the NO-signal pathway. Methods and Results-In rat neonatal cardiac myocytes, celiprolol inhibited protein synthesis stimulated by either isoproterenol or phenylephrine, which was partially suppressed by N-G-nitro-L-arginine methyl ester (L-NAME). Four weeks after transverse aortic constriction (TAC) in C57BL/6 male mice, the ratio of heart weight to body weight (mg/g) (8.70+/-0.42 in TAC, 6.61+/-0.44 with celiprolol 100 mg.kg(-1).d(-1) PO, P<0.01) and the ratio of lung weight to body weight (mg/g) (10.27&PLUSMN;1.08 in TAC, 7.11&PLUSMN;0.70 with celiprolol 100 mg.kg(-1).d(-1) PO, P<0.05) were lower and LV fractional shortening was higher in the celiprolol-treated groups than in the TAC group. All of these improvements were blunted by L-NAME. Celiprolol treatment significantly increased myocardial eNOS and activated phosphorylation of eNOS. Myocardial mRNA levels of natriuretic peptide precursor type B and protein inhibitor of NO synthase, which were increased in the TAC mice, were decreased in the celiprolol-treated mice. Conclusions-These findings indicated that celiprolol attenuates cardiac myocyte hypertrophy both in vitro and in vivo and halts the process leading from hypertrophy to heart failure. These effects are mediated by a selective beta(1)-adrenergic receptor blockade and NO-dependent pathway.
  • Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction - Possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis, K Okada, T Minamino, Y Tsukamoto, YL Liao, O Tsukamoto, S Takashima, A Hirata, M Fujita, Y Nagamachi, T Nakatani, C Yutani, K Ozawa, S Ogawa, H Tomoike, M Hori, M Kitakaze, CIRCULATION, 110, (6), 705 - 712,   2004年08月
    Background-The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear. Methods and Results-Mice were subjected to transverse aortic constriction (TAC) or sham operation. Echocardiographic analysis demonstrated that mice 1 and 4 weeks after TAC had cardiac hypertrophy and failure, respectively. Cardiac expression of ER chaperones was significantly increased 1 and 4 weeks after TAC, indicating that pressure overload by TAC induced prolonged ER stress. In addition, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells increased, and caspase-3 was cleaved in failing hearts. The antagonism of angiotensin II type 1 receptor prevented upregulation of ER chaperones and apoptosis in failing hearts. On the other hand, angiotensin II upregulated ER chaperones and induced apoptosis in cultured adult rat cardiac myocytes. We also investigated possible signaling pathways for ER-initiated apoptosis. The CHOP-(a transcription factor induced by ER stress), but not JNK- or caspase-12-, dependent pathway was activated in failing hearts by TAC. Pharmacological ER stress inducers upregulated ER chaperones and induced apoptosis in cultured cardiac myocytes. Finally, mRNA levels of ER chaperones were markedly increased in failing hearts of patients with elevated brain natriuretic peptide levels. Conclusions-These findings suggest that pressure overload by TAC induces prolonged ER stress, which may contribute to cardiac myocyte apoptosis during progression from cardiac hypertrophy to failure.
  • Celiprolol, a vasodilatory beta-blocker, inhibits pressure overload-induced cardiac hypertrophy and prevents the transition to heart failure via nitric oxide-dependent mechanisms in mice, YL Liao, M Asakura, S Takashima, A Ogai, Y Asano, Y Shintani, T Minamino, H Asanuma, S Sanada, J Kim, S Kitamura, H Tomoike, M Hori, M Kitakaze, CIRCULATION, 110, (6), 692 - 699,   2004年08月
    Background-The blockade of beta-adrenergic receptors reduces both mortality and morbidity in patients with chronic heart failure, but the cellular mechanism remains unclear. Celiprolol, a selective beta(1)-blocker, was reported to stimulate the expression of endothelial NO synthase (eNOS) in the heart, and NO levels have been demonstrated to be related to myocardial hypertrophy and heart failure. Thus, we aimed to clarify whether celiprolol attenuates both myocardial hypertrophy and heart failure via the NO-signal pathway. Methods and Results-In rat neonatal cardiac myocytes, celiprolol inhibited protein synthesis stimulated by either isoproterenol or phenylephrine, which was partially suppressed by N-G-nitro-L-arginine methyl ester (L-NAME). Four weeks after transverse aortic constriction (TAC) in C57BL/6 male mice, the ratio of heart weight to body weight (mg/g) (8.70+/-0.42 in TAC, 6.61+/-0.44 with celiprolol 100 mg.kg(-1).d(-1) PO, P<0.01) and the ratio of lung weight to body weight (mg/g) (10.27&PLUSMN;1.08 in TAC, 7.11&PLUSMN;0.70 with celiprolol 100 mg.kg(-1).d(-1) PO, P<0.05) were lower and LV fractional shortening was higher in the celiprolol-treated groups than in the TAC group. All of these improvements were blunted by L-NAME. Celiprolol treatment significantly increased myocardial eNOS and activated phosphorylation of eNOS. Myocardial mRNA levels of natriuretic peptide precursor type B and protein inhibitor of NO synthase, which were increased in the TAC mice, were decreased in the celiprolol-treated mice. Conclusions-These findings indicated that celiprolol attenuates cardiac myocyte hypertrophy both in vitro and in vivo and halts the process leading from hypertrophy to heart failure. These effects are mediated by a selective beta(1)-adrenergic receptor blockade and NO-dependent pathway.
  • Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction - Possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis, K Okada, T Minamino, Y Tsukamoto, YL Liao, O Tsukamoto, S Takashima, A Hirata, M Fujita, Y Nagamachi, T Nakatani, C Yutani, K Ozawa, S Ogawa, H Tomoike, M Hori, M Kitakaze, CIRCULATION, 110, (6), 705 - 712,   2004年08月
    Background-The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear. Methods and Results-Mice were subjected to transverse aortic constriction (TAC) or sham operation. Echocardiographic analysis demonstrated that mice 1 and 4 weeks after TAC had cardiac hypertrophy and failure, respectively. Cardiac expression of ER chaperones was significantly increased 1 and 4 weeks after TAC, indicating that pressure overload by TAC induced prolonged ER stress. In addition, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells increased, and caspase-3 was cleaved in failing hearts. The antagonism of angiotensin II type 1 receptor prevented upregulation of ER chaperones and apoptosis in failing hearts. On the other hand, angiotensin II upregulated ER chaperones and induced apoptosis in cultured adult rat cardiac myocytes. We also investigated possible signaling pathways for ER-initiated apoptosis. The CHOP-(a transcription factor induced by ER stress), but not JNK- or caspase-12-, dependent pathway was activated in failing hearts by TAC. Pharmacological ER stress inducers upregulated ER chaperones and induced apoptosis in cultured cardiac myocytes. Finally, mRNA levels of ER chaperones were markedly increased in failing hearts of patients with elevated brain natriuretic peptide levels. Conclusions-These findings suggest that pressure overload by TAC induces prolonged ER stress, which may contribute to cardiac myocyte apoptosis during progression from cardiac hypertrophy to failure.
  • Protein kinase A as another mediator of ischemic preconditioning independent of protein kinase C, S Sanada, H Asanuma, O Tsukamoto, T Minamino, K Node, S Takashima, T Fukushima, A Ogai, Y Shinozaki, M Fujita, A Hirata, H Okuda, H Shimokawa, H Tomoike, M Hori, M Kitakaze, CIRCULATION, 110, (1), 51 - 57,   2004年07月
    Background - We and others have reported that transient accumulation of cyclic AMP (cAMP) in the myocardium during ischemic preconditioning (IP) limits infarct size independent of protein kinase C (PKC). Accumulation of cAMP activates protein kinase A (PKA), which has been demonstrated to cause reversible inhibition of RhoA and Rho-kinase. We investigated the involvement of PKA and Rho-kinase in the infarct limitation by IP. Methods and Results - Dogs were subjected to 90-minute ischemia and 6-hour reperfusion. We examined the effect on Rho-kinase activity during sustained ischemia and infarct size of (1) preischemic transient coronary occlusion (IP), (2) preischemic activation of PKA/PKC, (3) inhibition of PKA/PKC during IP, and (4) inhibition of Rho-kinase or actin cytoskeletal deactivation during myocardial ischemia. Either IP or dibutyryl-cAMP treatment activated PKA, which was dose-dependently inhibited by 2 PKA inhibitors (H89 and Rp-cAMP). IP and preischemic PKA activation substantially reduced infarct size, which was blunted by preischemic PKA inhibition. IP and preischemic PKA activation, but not PKC activation, caused a substantial decrease of Rho-kinase activation during sustained ischemia. These changes were cancelled by preischemic inhibition of PKA but not PKC. Furthermore, either Rho-kinase inhibition (hydroxyfasudil or Y27632) or actin cytoskeletal deactivation (cytochalasin-D) during sustained ischemia achieved the same infarct limitation as preischemic PKA activation without affecting systemic hemodynamic parameters, the area at risk, or collateral blood flow. Conclusions - Transient preischemic activation of PKA reduces infarct size through Rho-kinase inhibition and actin cytoskeletal deactivation during sustained ischemia, implicating a novel mechanism for cardioprotection by ischemic preconditioning independent of PKC and a potential new therapeutic target.
  • Protein kinase A as another mediator of ischemic preconditioning independent of protein kinase C, S Sanada, H Asanuma, O Tsukamoto, T Minamino, K Node, S Takashima, T Fukushima, A Ogai, Y Shinozaki, M Fujita, A Hirata, H Okuda, H Shimokawa, H Tomoike, M Hori, M Kitakaze, CIRCULATION, 110, (1), 51 - 57,   2004年07月
    Background - We and others have reported that transient accumulation of cyclic AMP (cAMP) in the myocardium during ischemic preconditioning (IP) limits infarct size independent of protein kinase C (PKC). Accumulation of cAMP activates protein kinase A (PKA), which has been demonstrated to cause reversible inhibition of RhoA and Rho-kinase. We investigated the involvement of PKA and Rho-kinase in the infarct limitation by IP. Methods and Results - Dogs were subjected to 90-minute ischemia and 6-hour reperfusion. We examined the effect on Rho-kinase activity during sustained ischemia and infarct size of (1) preischemic transient coronary occlusion (IP), (2) preischemic activation of PKA/PKC, (3) inhibition of PKA/PKC during IP, and (4) inhibition of Rho-kinase or actin cytoskeletal deactivation during myocardial ischemia. Either IP or dibutyryl-cAMP treatment activated PKA, which was dose-dependently inhibited by 2 PKA inhibitors (H89 and Rp-cAMP). IP and preischemic PKA activation substantially reduced infarct size, which was blunted by preischemic PKA inhibition. IP and preischemic PKA activation, but not PKC activation, caused a substantial decrease of Rho-kinase activation during sustained ischemia. These changes were cancelled by preischemic inhibition of PKA but not PKC. Furthermore, either Rho-kinase inhibition (hydroxyfasudil or Y27632) or actin cytoskeletal deactivation (cytochalasin-D) during sustained ischemia achieved the same infarct limitation as preischemic PKA activation without affecting systemic hemodynamic parameters, the area at risk, or collateral blood flow. Conclusions - Transient preischemic activation of PKA reduces infarct size through Rho-kinase inhibition and actin cytoskeletal deactivation during sustained ischemia, implicating a novel mechanism for cardioprotection by ischemic preconditioning independent of PKC and a potential new therapeutic target.
  • b-adrenoceptor blocker carvedilol provides cardioprotection via an adenosine-dependent mechanism in ischemic canine hearts, H Asanuma, T Minamino, S Sanada, S Takashima, H Ogita, A Ogai, M Asakura, YL Liao, Y Asano, Y Shintani, J Kim, Y Shinozaki, H Mori, K Node, S Kitamura, H Tomoike, M Hori, M Kitakaze, CIRCULATION, 109, (22), 2773 - 2779,   2004年06月
    Background - Carvedilol is a beta-adrenoceptor blocker with a vasodilatory action that is more effective for the treatment of congestive heart failure than other beta-blockers. Recently, carvedilol has been reported to reduce oxidative stress, which may consequently reduce the deactivation of adenosine-producing enzymes and increase cardiac adenosine levels. Therefore, carvedilol may also have a protective effect on ischemia and reperfusion injury, because adenosine mediates cardioprotection in ischemic hearts. Methods and Results - In anesthetized dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Carvedilol reduced the infarct size (15.0 +/- 2.8% versus 40.9 +/- 4.2% in controls), and this effect was completely reversed by the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (45.2 +/- 5.4%) or by an inhibitor of ecto-5'-nucleotidase (44.4 +/- 3.6%). There were no differences of either area at risk or collateral flow among the various groups. When the coronary perfusion pressure was reduced in other dogs so that coronary blood flow was decreased to 50% of the nonischemic level, carvedilol increased coronary blood flow (49.4 +/- 5.6 to 73.5 +/- 7.5 mL . 100 g(-1) . min(-1); P < 0.05) and adenosine release ( 112.3 +/- 22.2 to 240.6 +/- 57.1 nmol/L; P < 0.05) during coronary hypoperfusion. This increase of coronary blood flow was attenuated by either 8-sulfophenyltheophylline or superoxide dismutase. In human umbilical vein endothelial cells cultured with or without xanthine and xanthine oxidase, carvedilol caused an increase of ecto-5'-nucleotidase activity. Conclusions - Carvedilol shows a cardioprotective effect against ischemia and/or reperfusion injury via adenosine-dependent mechanisms.
  • b-adrenoceptor blocker carvedilol provides cardioprotection via an adenosine-dependent mechanism in ischemic canine hearts, H Asanuma, T Minamino, S Sanada, S Takashima, H Ogita, A Ogai, M Asakura, YL Liao, Y Asano, Y Shintani, J Kim, Y Shinozaki, H Mori, K Node, S Kitamura, H Tomoike, M Hori, M Kitakaze, CIRCULATION, 109, (22), 2773 - 2779,   2004年06月
    Background - Carvedilol is a beta-adrenoceptor blocker with a vasodilatory action that is more effective for the treatment of congestive heart failure than other beta-blockers. Recently, carvedilol has been reported to reduce oxidative stress, which may consequently reduce the deactivation of adenosine-producing enzymes and increase cardiac adenosine levels. Therefore, carvedilol may also have a protective effect on ischemia and reperfusion injury, because adenosine mediates cardioprotection in ischemic hearts. Methods and Results - In anesthetized dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Carvedilol reduced the infarct size (15.0 +/- 2.8% versus 40.9 +/- 4.2% in controls), and this effect was completely reversed by the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (45.2 +/- 5.4%) or by an inhibitor of ecto-5'-nucleotidase (44.4 +/- 3.6%). There were no differences of either area at risk or collateral flow among the various groups. When the coronary perfusion pressure was reduced in other dogs so that coronary blood flow was decreased to 50% of the nonischemic level, carvedilol increased coronary blood flow (49.4 +/- 5.6 to 73.5 +/- 7.5 mL . 100 g(-1) . min(-1); P < 0.05) and adenosine release ( 112.3 +/- 22.2 to 240.6 +/- 57.1 nmol/L; P < 0.05) during coronary hypoperfusion. This increase of coronary blood flow was attenuated by either 8-sulfophenyltheophylline or superoxide dismutase. In human umbilical vein endothelial cells cultured with or without xanthine and xanthine oxidase, carvedilol caused an increase of ecto-5'-nucleotidase activity. Conclusions - Carvedilol shows a cardioprotective effect against ischemia and/or reperfusion injury via adenosine-dependent mechanisms.
  • Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice, H Ogita, K Node, YL Liao, F Ishikura, S Beppu, H Asanuma, S Sanada, S Takashima, T Minamino, M Hori, M Kitakaze, HYPERTENSION, 43, (2), 237 - 242,   2004年02月
    17beta-Estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [H-3] leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein ( MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [H-3] leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N-G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent.
  • Lamr1 functional retroposon causes right ventricular dysplasia in mice, Y Asano, S Takashima, M Asakura, Y Shintani, YL Liao, T Minamino, H Asanuma, S Sanada, J Kim, A Ogai, T Fukushima, Y Oikawa, Y Okazaki, Y Kaneda, M Sato, J Miyazaki, S Kitamura, H Tomoike, M Kitakaze, M Hori, NATURE GENETICS, 36, (2), 123 - 130,   2004年02月
    Arrhythmogenic right ventricular dysplasia (ARVD) is a hereditary cardiomyopathy that causes sudden death in the young. We found a line of mice with inherited right ventricular dysplasia (RVD) caused by a mutation of the gene laminin receptor 1 (Lamr1). This locus contained an intron-processed retroposon that was transcribed in the mice with RVD. Introduction of a mutated Lamr1 gene into normal mice by breeding or by direct injection caused susceptibility to RVD, which was similar to that seen in the RVD mice. An in vitro study of cardiomyocytes expressing the product of mutated Lamr1 showed early cell death accompanied by alteration of the chromatin architecture. We found that heterochromatin protein 1 ( HP1) bound specifically to mutant LAMR1. HP1 is a dynamic regulator of heterochromatin sites, suggesting that mutant LAMR1 impairs a crucial process of transcriptional regulation. Indeed, mutant LAMR1 caused specific changes to gene expression in cardiomyocytes, as detected by gene chip analysis. Thus, we concluded that products of the Lamr1 retroposon interact with HP1 to cause degeneration of cardiomyocytes. This mechanism may also contribute to the etiology of human ARVD.
  • Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice, H Ogita, K Node, YL Liao, F Ishikura, S Beppu, H Asanuma, S Sanada, S Takashima, T Minamino, M Hori, M Kitakaze, HYPERTENSION, 43, (2), 237 - 242,   2004年02月
    17beta-Estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [H-3] leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein ( MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [H-3] leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N-G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent.
  • Lamr1 functional retroposon causes right ventricular dysplasia in mice, Y Asano, S Takashima, M Asakura, Y Shintani, YL Liao, T Minamino, H Asanuma, S Sanada, J Kim, A Ogai, T Fukushima, Y Oikawa, Y Okazaki, Y Kaneda, M Sato, J Miyazaki, S Kitamura, H Tomoike, M Kitakaze, M Hori, NATURE GENETICS, 36, (2), 123 - 130,   2004年02月
    Arrhythmogenic right ventricular dysplasia (ARVD) is a hereditary cardiomyopathy that causes sudden death in the young. We found a line of mice with inherited right ventricular dysplasia (RVD) caused by a mutation of the gene laminin receptor 1 (Lamr1). This locus contained an intron-processed retroposon that was transcribed in the mice with RVD. Introduction of a mutated Lamr1 gene into normal mice by breeding or by direct injection caused susceptibility to RVD, which was similar to that seen in the RVD mice. An in vitro study of cardiomyocytes expressing the product of mutated Lamr1 showed early cell death accompanied by alteration of the chromatin architecture. We found that heterochromatin protein 1 ( HP1) bound specifically to mutant LAMR1. HP1 is a dynamic regulator of heterochromatin sites, suggesting that mutant LAMR1 impairs a crucial process of transcriptional regulation. Indeed, mutant LAMR1 caused specific changes to gene expression in cardiomyocytes, as detected by gene chip analysis. Thus, we concluded that products of the Lamr1 retroposon interact with HP1 to cause degeneration of cardiomyocytes. This mechanism may also contribute to the etiology of human ARVD.
  • Erythropoetin Reduces Myocardial Infarct Size via Akt-dependent pathway, 10th International Symposium on Adenosine, Cardioprotection and Its Clinical Application,   2004年
  • Endoplasmic reticulum-initiated apoptosis via CHOP/GADD153-dependent pathway contributes to the development of heart failure, Circulation,   2004年
  • Rationale and design of a large-scale trial using nicorandil as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the reduction of Necrotic Dam・・・, Circ J,   2004年
    Rationale and design of a large-scale trial using nicorandil as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the reduction of Necrotic Damage by a K-ATP channel opener (J-WIND-KATP).
  • Rationale and design of a large-scale trial using atrial natriuretic peptide (ANP) as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the red・・・, Circ J,   2004年
    Rationale and design of a large-scale trial using atrial natriuretic peptide (ANP) as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the reduction of Necrotic Damage by ANP (J-WIND-ANP).
  • Methotrexate and MX-68, a new derivative of methotrexate, limit infarct size via adenosine-dependent mechanisms in canine hearts., J Cardiovasc Pharmacol,   2004年
  • Roles of systemic nitric oxide metabolites for human coronary circulation.,   2004年
  • Raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism in the ischemic heart: role of phosphatidylinositol 3-kinase/Akt pathway.,   2004年
  • Rationale and design of a large-scale trial using atrial natriuretic peptide (ANP) as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the red・・・, Circ J,   2004年
    Rationale and design of a large-scale trial using atrial natriuretic peptide (ANP) as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the reduction of Necrotic Damage by ANP (J-WIND-ANP).
  • Rationale and design of a large-scale trial using nicorandil as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the reduction of Necrotic Dam・・・, Circ J,   2004年
    Rationale and design of a large-scale trial using nicorandil as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the reduction of Necrotic Damage by a K-ATP channel opener (J-WIND-KATP).
  • Methotrexate and MX-68, a new derivative of methotrexate, limit infarct size via adenosine-dependent mechanisms in canine hearts., J Cardiovasc Pharmacol,   2004年
  • Roles of systemic nitric oxide metabolites for human coronary circulation.,   2004年
  • Raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism in the ischemic heart: role of phosphatidylinositol 3-kinase/Akt pathway.,   2004年
  • A calcium channel blocker activates both ecto-5'-nucleotidase and NO synthase in HUVEC, Y Asano, J Kim, A Ogai, S Takashima, Y Shintani, T Minamino, S Kitamura, H Tomoike, M Hori, M Kitakaze, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 311, (3), 625 - 628,   2003年11月
    Since amlodipine, a long-acting Ca channel blocker, increases both NO and adenosine production in canine hearts, we investigated that amlodipine activates both ecto-5'-nucleotidase responsible for adenosine production and NO synthase (NOS) for NO production in human umbilical venous endothelial cells (HUVECs), and its cellular signaling. We measured activities of ecto-5'-nucleotidase and NOS in HUVECs in the condition with additions of xanthine (100 muM) + xanthine oxidase (1.6 x 10(-3) U/ml) in the presence or absence of amlodipine (1 x 10(-9)-1 x 10(-6) M). Amlodipine increased both ecto-5'-nucleotidase and NOS activities. Xanthine + xanthine oxidase deactivated both NOS and ecto-5'-nucleotidase, and amlodipine increased both activities of NOS and ecto-5'-nucleotidase by 117 +/- 33% and 48 +/- 6%, respectively. Amlodipine phosphorylated p38MAP kinase and that an inhibitor of p38MAP kinase inhibited the amlodipine-induced activation of both NOS and ecto-5'-nucleotidase. Furthermore, amlodipine increased both adenosine and NO production in the canine ischemic hearts. We concluded that amlodipine activates both NOS and ecto-5'-nucleotidase via p38MAP kinase in vitro and enhances both NO and adenosine production in vivo. (C) 2003 Elsevier Inc. All rights reserved.
  • Activation of adenosine A(1) receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model, YL Liao, S Takashima, Y Asano, M Asakura, A Ogai, Y Shintani, T Minamino, H Asanuma, S Sanada, J Kim, H Ogita, H Tomoike, M Hori, M Kitakaze, CIRCULATION RESEARCH, 93, (8), 759 - 766,   2003年10月
    Sympathomimetic stimulation, angiotensin II, or endothelin-1 is considered to be an essential stimulus mediating ventricular hypertrophy. Adenosine is known to protect the heart from excessive catecholamine exposure, reduce production of endothelin-1, and attenuate the activation of the renin-angiotensin system. These findings suggest that adenosine may also attenuate myocardial hypertrophy. To verify this hypothesis, we examined whether activation of adenosine receptors can attenuate cardiac hypertrophy and reduce the risk of heart failure. Our in vitro study of neonatal rat cardiomyocytes showed that 2-chloroadenosine (CADO), a stable adenosine analogue, inhibits protein synthesis of cardiomyocytes induced by phenylephrine, endothelin-1, angiotensin II, or isoproterenol, which were mimicked by the stimulation of adenosine A(1) receptors. For our in vivo study, cardiac hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6 male mice. Four weeks after TAC, both heart to body weight ratio (6.80+/-0.18 versus 8.34+/-0.33 mg/g, P<0.0001) as well as lung to body weight ratio (6.23+/-0.27 versus 10.03+/-0.85 mg/g, P<0.0001) became significantly lower in CADO-treated mice than in the TAC group. Left ventricular fractional shortening and left ventricular dP/dt(max) were improved significantly by CADO treatment. Similar results were obtained using the selective adenosine A(1) agonist N-6-cyclopentyladenosine (CPA). A nonselective adenosine antagonist, 8-(p-sulfophenyl)-theophylline, and a selective adenosine A(1) antagonist, 8-cyclopentyl-1,3-dipropylxanthine, eliminated the antihypertrophic effect of CADO and CPA, respectively. The plasma norepinephrine level was decreased and myocardial expression of regulator of G protein signaling 4 was upregulated in CADO-treated mice. These results indicate that the stimulation of adenosine receptors attenuates both the cardiac hypertrophy and myocardial dysfunction via adenosine A(1) receptor-mediated mechanisms.
  • Long-acting Ca2+ blockers prevent myocardial remodeling induced by chronic NO inhibition in rats, S Sanada, K Node, T Minamino, S Takashima, A Ogai, H Asanuma, H Ogita, YL Liao, M Asakura, J Kim, M Hori, M Kitakaze, HYPERTENSION, 41, (4), 963 - 967,   2003年04月
    Chronic inhibition of nitric oxide (NO) synthesis induces cardiac remodeling independent of systemic hemodynamic changes in rats. We examined whether long-acting dihydropyridine calcium channel blockers block myocardial remodeling and whether the activation of 70-kDa S6 kinase (p70S6K) and extracellular signal-regulated kinase (ERK) are involved. Ten groups of Wistar-Kyoto rats underwent 8 weeks of drug treatment consisting of a combination of NO synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME), an inactive isomer (D-NAME), amlodipine (1 or 3 mg/kg per day), or benidipine (3 or 10 mg/kg per day). In other groups, L-NAME was also used in combination with a p70S6K inhibitor (rapamycin), a MEK inhibitor (PD98059), and hydralazine. Systolic blood pressure (SBP), heart rate, and left ventricular weight (LVW) were measured, together with histological examinations and kinase assay. L-NAME increased SBP and LVW (1048+/-22 versus 780+/-18 mg, P<0.01) compared with the control, showing a significant increase in cross-sectional area of cardiomyocytes after 8 weeks. Amlodipine, benidipine, or hydralazine equally attenuated the increase in SBP induced by L-NAME. However, both amlodipine and benidipine but not hydralazine attenuated the increase in LVW by L-NAME (789+/-27, 825+/-20 mg, P<0.01, and 1118+/-29 mg, NS, respectively), also confirmed by histological analysis. L-NAME caused a 2.2-fold/1.8-fold increase in p70S6K/ERK activity in myocardium compared with the control, both of which were attenuated by both amlodipine and benidipine but not hydralazine. Both rapamycin and PD98059 attenuated cardiac hypertrophy in this model. Thus, long-acting dihydropyridine calcium channel blockers inhibited cardiac hypertrophy induced by chronic inhibition of NO synthesis by inhibiting both p70S6K and ERK in vivo.
  • Long-acting Ca2+ blockers prevent myocardial remodeling induced by chronic NO inhibition in rats, S Sanada, K Node, T Minamino, S Takashima, A Ogai, H Asanuma, H Ogita, YL Liao, M Asakura, J Kim, M Hori, M Kitakaze, HYPERTENSION, 41, (4), 963 - 967,   2003年04月
    Chronic inhibition of nitric oxide (NO) synthesis induces cardiac remodeling independent of systemic hemodynamic changes in rats. We examined whether long-acting dihydropyridine calcium channel blockers block myocardial remodeling and whether the activation of 70-kDa S6 kinase (p70S6K) and extracellular signal-regulated kinase (ERK) are involved. Ten groups of Wistar-Kyoto rats underwent 8 weeks of drug treatment consisting of a combination of NO synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME), an inactive isomer (D-NAME), amlodipine (1 or 3 mg/kg per day), or benidipine (3 or 10 mg/kg per day). In other groups, L-NAME was also used in combination with a p70S6K inhibitor (rapamycin), a MEK inhibitor (PD98059), and hydralazine. Systolic blood pressure (SBP), heart rate, and left ventricular weight (LVW) were measured, together with histological examinations and kinase assay. L-NAME increased SBP and LVW (1048+/-22 versus 780+/-18 mg, P<0.01) compared with the control, showing a significant increase in cross-sectional area of cardiomyocytes after 8 weeks. Amlodipine, benidipine, or hydralazine equally attenuated the increase in SBP induced by L-NAME. However, both amlodipine and benidipine but not hydralazine attenuated the increase in LVW by L-NAME (789+/-27, 825+/-20 mg, P<0.01, and 1118+/-29 mg, NS, respectively), also confirmed by histological analysis. L-NAME caused a 2.2-fold/1.8-fold increase in p70S6K/ERK activity in myocardium compared with the control, both of which were attenuated by both amlodipine and benidipine but not hydralazine. Both rapamycin and PD98059 attenuated cardiac hypertrophy in this model. Thus, long-acting dihydropyridine calcium channel blockers inhibited cardiac hypertrophy induced by chronic inhibition of NO synthesis by inhibiting both p70S6K and ERK in vivo.
  • Ablation of MEKK1 prevents cardiac hypertrophy and dysfunction by Gq, 第7回日本心不全学会学術集会 シンポジウム ,   2003年
  • Celiprolol increases coronary blood flow and reduces severity of myocardial ischemia via nitric oxide release., J Cardiovasc Pharmacol, 41(4):499-505,   2003年
  • Eicosapentaenoic acid reduces myocardial injury induced by ischemia and reperfusion in rabbit hearts., J Cardiovasc Pharmacol., 41(6):964-9.,   2003年
  • Canine DNA array as a potential tool for combining physiology and molecular biology, Circ J, 67(9):788-92,   2003年
  • Signal transduction study using gene-targeted embryonic stem cells, Methods Mol Biol, 218:35-46,   2003年
  • Celiprolol increases coronary blood flow and reduces severity of myocardial ischemia via nitric oxide release., J Cardiovasc Pharmacol, 41(4):499-505,   2003年
  • Signal transduction study using gene-targeted embryonic stem cells, Methods Mol Biol, 218:35-46,   2003年
  • MEKK1 is essential for cardiac hypertrophy and dysfunction induced by Gq, T Minamino, T Yujiri, N Terada, GE Taffet, LH Michael, GL Johnson, MD Schneider, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 99, (6), 3866 - 3871,   2002年03月
    Signaling via mitogen-activated protein kinases is implicated in heart failure induced by agonists for G protein-coupled receptors that act via the G protein Galphaq. However, this assertion relies heavily on pharmacological inhibitors and dominant-interfering proteins and not on gene deletion. Here, we show that endogenous cardiac MAPK/ERK kinase kinase-1 (MEKK1)/(MAP3K1), a mitogen-activated protein kinase kinase kinase, is activated by heart-restricted overexpression of Galphaq in mice. In cardiac myocytes derived from embryonic stem cells in culture, homozygous disruption of MEKK1 selectively impaired c-Jun N-terminal kinase activity in the absence or presence of phenlyephrine, a Galphaq-dependent agonist. Other terminal mitogen-activated protein kinases were unaffected. In mice, the absence of MEKK1 abolished the increase in cardiac mass, myocyte size, hypertrophy-associated atrial natriuretic factor induction, and c-Jun N-terminal kinase activation by Galphaq, and improved ventricular mechanical function. Thus, MEKK1 mediates cardiac hypertrophy induced by Galphaq in vivo and is a logical target for drug development in heart disease involving this pathway.
  • MEKK1 is essential for cardiac hypertrophy and dysfunction induced by Gq, T Minamino, T Yujiri, N Terada, GE Taffet, LH Michael, GL Johnson, MD Schneider, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 99, (6), 3866 - 3871,   2002年03月
    Signaling via mitogen-activated protein kinases is implicated in heart failure induced by agonists for G protein-coupled receptors that act via the G protein Galphaq. However, this assertion relies heavily on pharmacological inhibitors and dominant-interfering proteins and not on gene deletion. Here, we show that endogenous cardiac MAPK/ERK kinase kinase-1 (MEKK1)/(MAP3K1), a mitogen-activated protein kinase kinase kinase, is activated by heart-restricted overexpression of Galphaq in mice. In cardiac myocytes derived from embryonic stem cells in culture, homozygous disruption of MEKK1 selectively impaired c-Jun N-terminal kinase activity in the absence or presence of phenlyephrine, a Galphaq-dependent agonist. Other terminal mitogen-activated protein kinases were unaffected. In mice, the absence of MEKK1 abolished the increase in cardiac mass, myocyte size, hypertrophy-associated atrial natriuretic factor induction, and c-Jun N-terminal kinase activation by Galphaq, and improved ventricular mechanical function. Thus, MEKK1 mediates cardiac hypertrophy induced by Galphaq in vivo and is a logical target for drug development in heart disease involving this pathway.
  • Prolonged ER stress in hypertrophic and failing hearts following aortic constriction: Possible contr, 米国心臓協会(AHA)Outstanding Early Career Investigator Award,   2002年
  • Cellular mechanisms for the treatment of chronic heart failure: the nitric oxide- and adenosine-dependent pathways., Expert Opin Emerg Drugs,   2002年
  • Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis: role of 70-kDa S6 kinase and extracellular signal-regulated kinase, J Am Coll Cardiol., 96(5):497-505,   2002年
  • Cellular mechanisms for the treatment of chronic heart failure: The nitric oxide- and adenosine-dependent pathways, Tetsuo Minamino, Masafumi Kitakaze, Expert Opinion on Emerging Drugs, 7, (1), 99 - 110,   2002年
    Accumulated evidence suggests that several drugs proven to improve survival in patients with chronic heart failure (CHF) enhance endogenous nitric oxide (NO)- and/or adenosine-dependent pathways. Indeed, we and others have demonstrated that: i) antagonists of either renin-angiotensin-aldosterone or β-adrenergic systems enhance NO-dependent pathways ii) although carvedilol and amlodipine belong to different drug classes, both of them can increase cardiac adenosine levels iii) increased adenosine levels by dipyridamole are associated with the improvement of CHF. Interestingly, both NO and adenosine have multifactorial beneficial actions in cardiovascular systems. First of all, both of them induce vasodilation and decrease myocardial hyper-contractility, which may contribute to a reduction in the severity of myocardial ischaemia. Both adenosine and NO are also involved in cardioprotection attributable to acute and late phases of ischaemic preconditioning, respectively. Secondly, they can modulate the neurohormonal systems that contribute to the progression of CHF. Thus, we propose that enhancement of endogenous NO and/or adenosine as potential therapeutic targets in a new strategy for the treatment for CHF.
  • Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis: role of 70-kDa S6 kinase and extracellular signal-regulated kinase, J Am Coll Cardiol., 96(5):497-505,   2002年
  • Conditional Transgenesis, Kluwer Academic Publishers,   2001年
  • Inducible gene targeting in postnatal myocardium by cardiac-specific expression of a hormone-activated Cre fusion protein., Circ Res., 88(6):587-92,   2001年
  • Differential subcellular actions of ACE inhibitors and AT(1) receptor antagonists on cardiac remodeling induced by chronic inhibition of NO synthesis in rats., Hypertension., 38(3):404-11,   2001年
  • Nifedipine limits infarct size via NO-dependent mechanisms in dogs, Basic Res Cardiol, 96(5):497-505,   2001年
  • Inducible gene targeting in postnatal myocardium by cardiac-specific expression of a hormone-activated Cre fusion protein., Circ Res., 88(6):587-92,   2001年
  • Differential subcellular actions of ACE inhibitors and AT(1) receptor antagonists on cardiac remodeling induced by chronic inhibition of NO synthesis in rats., Hypertension., 38(3):404-11,   2001年
  • Nifedipine limits infarct size via NO-dependent mechanisms in dogs, Basic Res Cardiol, 96(5):497-505,   2001年
  • Nifedipine-induced coronary vasodilation in ischemic hearts is attributable to bradykinin- and NO-dependent mechanisms in dogs., Circulation., 101(3):311-7.,   2000年
  • Cellular mechanisms of cardioprotection afforded by inhibitors of angiotensin converting enzyme in ischemic hearts: role of bradykinin and nitric oxide., Hypertens Res, 23(3):253-9,   2000年
  • Chronic treatment with FK506 increases p70 S6 kinase activity associated with reduced nitric oxide synthase activity in rabbit hearts., Cardiovasc Drugs Ther, 14(3):329-36.,   2000年
  • Inhibition of nitric oxide synthesis induces coronary vascular remodeling and cardiac hypertrophy associated with the activation of p70 S6 kinase in rats.,   2000年
  • Nifedipine-induced coronary vasodilation in ischemic hearts is attributable to bradykinin- and NO-dependent mechanisms in dogs., Circulation., 101(3):311-7.,   2000年
  • Cellular mechanisms of cardioprotection afforded by inhibitors of angiotensin converting enzyme in ischemic hearts: role of bradykinin and nitric oxide., Hypertens Res, 23(3):253-9,   2000年
  • Chronic treatment with FK506 increases p70 S6 kinase activity associated with reduced nitric oxide synthase activity in rabbit hearts., Cardiovasc Drugs Ther, 14(3):329-36.,   2000年
  • Inhibition of nitric oxide synthesis induces coronary vascular remodeling and cardiac hypertrophy associated with the activation of p70 S6 kinase in rats.,   2000年
  • Genetic disruption of MEKK1 accelerates cardiac apoptotic cell death by oxidative stress through inc, 米国心臓協会(AHA)Melvin Marcus Young Investigator Award,   1999年
  • 心房細動患者の脳血栓・塞栓症発症における血小板P- セレクチン発現増加の意義, 第63回日本循環器学会総会・学術集会/シンポジウム<心房細動への多角的アプローチ>,   1999年
  • A Ca channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependent mechanisms in dogs., J Am Coll Cardiol, 33(1):242-9,   1999年
  • Plasma adenosine levels and platelet activation in patients with atrial fibrillation., Am J Cardiol, 83(2):194-8,   1999年
  • Glycoprotein IIb/IIIa antagonist FK633 could not prevent neointimal thickening in stent implantation model of canine coronary artery., Arterioscler Thromb Vasc Biol, 19(2):343-7,   1999年
  • [Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide], J Cardiol, 12(6):533-41,   1999年
  • Adenosine and cardioprotection in the diseased heart, Jpn Circ J, 63(4):231-43,   1999年
  • Improvement by 5-amino-4-imidazole carboxamide riboside of the contractile dysfunction that follows brief periods of ischemia through increases in ecto-5-nucleotidase activity and adenosine release in canine hearts., Jpn Circ J, 63(7):542-53,   1999年
  • Intracoronary administration of adenosine triphosphate increases coronary blood flow and attenuates the severity of myocardial ischemic injury in dogs., Cardiovasc Drugs Ther., 13(5):407-14,   1999年
  • Increased membrane and soluble P-selectin in atrial fibrillation., Circulation,   1999年
  • Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction., J Am Coll Cardiol., 34(7):2120-5,   1999年
  • MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes., Proc Natl Acad Sci U S A, 96(26):15127-32.,   1999年
  • A Ca channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependent mechanisms in dogs., J Am Coll Cardiol, 33(1):242-9,   1999年
  • Plasma adenosine levels and platelet activation in patients with atrial fibrillation., Am J Cardiol, 83(2):194-8,   1999年
  • Glycoprotein IIb/IIIa antagonist FK633 could not prevent neointimal thickening in stent implantation model of canine coronary artery., Arterioscler Thromb Vasc Biol, 19(2):343-7,   1999年
  • [Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide], J Cardiol, 12(6):533-41,   1999年
  • Adenosine and cardioprotection in the diseased heart, Jpn Circ J, 63(4):231-43,   1999年
  • Improvement by 5-amino-4-imidazole carboxamide riboside of the contractile dysfunction that follows brief periods of ischemia through increases in ecto-5-nucleotidase activity and adenosine release in canine hearts., Jpn Circ J, 63(7):542-53,   1999年
  • Intracoronary administration of adenosine triphosphate increases coronary blood flow and attenuates the severity of myocardial ischemic injury in dogs., Cardiovasc Drugs Ther., 13(5):407-14,   1999年
  • Increased membrane and soluble P-selectin in atrial fibrillation., Circulation,   1999年
  • Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction., J Am Coll Cardiol., 34(7):2120-5,   1999年
  • MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes., Proc Natl Acad Sci U S A, 96(26):15127-32.,   1999年
  • 心房細動患者の脳血栓・塞栓症発症における血小板P-セレクチン発現増加の意義, 第46回日本心臓病学会学術集会 Young Investigator Awards,   1998年
  • Endogenous adenosine inhibits P-selectin-dependent formation of coronary thromboemboli during hypoperfusion in dogs., J Clin Invest, 101(8):1643-53,   1998年
  • Impact of coronary risk factors on contribution of nitric oxide and adenosine to metabolic coronary vasodilation in humans., J Am Coll Cardiol., 31(6):1274-9,   1998年
  • Role of Ca2+-activated K+ channels in the protective effect of ACE inhibition against ischemic myocardial injury., Hypertension, 31(6):1290-8,   1998年
  • Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide., Circulation, 98(17):1721-7,   1998年
  • Inhibition of angiotensin-converting enzyme increases the nitric oxide levels in canine ischemic myocardium., J Mol Cell Cardiol, 30(11):2461-6,   1998年
  • Nisoldipine selectively induces coronary vasodilation and improves mild myocardial ischemia in dogs: a potential role of cellular acidosis., Cardiovasc Drugs Ther., 12(6):533-41,   1998年
  • Endogenous adenosine inhibits P-selectin-dependent formation of coronary thromboemboli during hypoperfusion in dogs., J Clin Invest, 101(8):1643-53,   1998年
  • Impact of coronary risk factors on contribution of nitric oxide and adenosine to metabolic coronary vasodilation in humans., J Am Coll Cardiol., 31(6):1274-9,   1998年
  • Role of Ca2+-activated K+ channels in the protective effect of ACE inhibition against ischemic myocardial injury., Hypertension, 31(6):1290-8,   1998年
  • Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide., Circulation, 98(17):1721-7,   1998年
  • Inhibition of angiotensin-converting enzyme increases the nitric oxide levels in canine ischemic myocardium., J Mol Cell Cardiol, 30(11):2461-6,   1998年
  • Nisoldipine selectively induces coronary vasodilation and improves mild myocardial ischemia in dogs: a potential role of cellular acidosis., Cardiovasc Drugs Ther., 12(6):533-41,   1998年
  • 白血球, “心筋障害と心筋保護”(医学書院),   1997年
  • Activation of ecto-5'-nucleotidase by protein kinase C and its role in ischaemic tolerance in the canine heart., Br J Pharmacol., 120(2):273-81.,   1997年
  • Effect of theophylline on adaptation of the heart to myocardial ischemia during percutaneous transluminal coronary angioplasty in patients with stable angina pectoris., Am J Cardiol., 79(4):475-7.,   1997年
  • Plasma adenosine levels increase in patients with chronic heart failure., Circulation., 95(6):1363-5,   1997年
  • Bradykinin mediation of Ca(2+)-activated K+ channels regulates coronary blood flow in ischemic myocardium., Circulation., 95(6):1560-7.,   1997年
  • Vesnarinone limits infarct size via adenosine-dependent mechanisms in the canine heart., Circulation., 95(8):2108-14.,   1997年
  • Temporary acidosis during reperfusion limits myocardial infarct size in dogs., Am J Physiol., 272(5 Pt 2):H2071-8,   1997年
  • Roles of NO and Ca2+-activated K+ channels in coronary vasodilation induced by 17beta-estradiol in ischemic heart failure., FASEB J, 11(10):793-9,   1997年
  • Role of intracellular Ca2+ in activation of protein kinase C during ischemic preconditioning., Circulation., 96(4):1257-65,   1997年
  • Inhibition of nitric oxide synthesis increases adenosine production via an extracellular pathway through activation of protein kinase C., Circulation., 96(5):1586-92,   1997年
  • Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: role of nitric oxide and calcium-activated potassium channels., Circulation, 96(6):1953-63,   1997年
  • Role of protein kinase C-alpha in activation of ecto-5'-nucleotidase in the preconditioned canine myocardium., Biochem Biophys Res Commun., 239(1):171-5.,   1997年
  • Plasma levels of nitrite/nitrate and platelet cGMP levels are decreased in patients with atrial fibrillation., Arterioscler Thromb Vasc Biol, 17(11):3191-5,   1997年
  • Ecto-5'-nucleotidase mediates infarct size-limiting effect by ischemic preconditioning in the rabbit heart., J Cardiovasc Pharmacol, 30(6):775-83,   1997年
  • Vesnarinone inhibits adenosine uptake in endothelial cells, smooth muscle cells and myocytes, and mediates cytoprotection., J Mol Cell Cardiol., 29(12):3413-7,   1997年
  • Activation of ecto-5'-nucleotidase by protein kinase C and its role in ischaemic tolerance in the canine heart., Br J Pharmacol., 120(2):273-81.,   1997年
  • Effect of theophylline on adaptation of the heart to myocardial ischemia during percutaneous transluminal coronary angioplasty in patients with stable angina pectoris., Am J Cardiol., 79(4):475-7.,   1997年
  • Plasma adenosine levels increase in patients with chronic heart failure., Circulation., 95(6):1363-5,   1997年
  • Bradykinin mediation of Ca(2+)-activated K+ channels regulates coronary blood flow in ischemic myocardium., Circulation., 95(6):1560-7.,   1997年
  • Vesnarinone limits infarct size via adenosine-dependent mechanisms in the canine heart., Circulation., 95(8):2108-14.,   1997年
  • Temporary acidosis during reperfusion limits myocardial infarct size in dogs., Am J Physiol., 272(5 Pt 2):H2071-8,   1997年
  • Roles of NO and Ca2+-activated K+ channels in coronary vasodilation induced by 17beta-estradiol in ischemic heart failure., FASEB J, 11(10):793-9,   1997年
  • Role of intracellular Ca2+ in activation of protein kinase C during ischemic preconditioning., Circulation., 96(4):1257-65,   1997年
  • Inhibition of nitric oxide synthesis increases adenosine production via an extracellular pathway through activation of protein kinase C., Circulation., 96(5):1586-92,   1997年
  • Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: role of nitric oxide and calcium-activated potassium channels., Circulation, 96(6):1953-63,   1997年
  • Role of protein kinase C-alpha in activation of ecto-5'-nucleotidase in the preconditioned canine myocardium., Biochem Biophys Res Commun., 239(1):171-5.,   1997年
  • Plasma levels of nitrite/nitrate and platelet cGMP levels are decreased in patients with atrial fibrillation., Arterioscler Thromb Vasc Biol, 17(11):3191-5,   1997年
  • Ecto-5'-nucleotidase mediates infarct size-limiting effect by ischemic preconditioning in the rabbit heart., J Cardiovasc Pharmacol, 30(6):775-83,   1997年
  • Vesnarinone inhibits adenosine uptake in endothelial cells, smooth muscle cells and myocytes, and mediates cytoprotection., J Mol Cell Cardiol., 29(12):3413-7,   1997年
  • Activation of ecto-5'-nucleotidase and cardioprotection by ischemic preconditioning., Basic Res Cardiol., 91(1):23-6,   1996年
  • Cardioprotection due to preconditioning correlates with increased ecto-5'-nucleotidase activity., Am J Physiol., 270(1 Pt 2):H238-44,   1996年
  • Increased release of NO during ischemia reduces myocardial contractility and improves metabolic dysfunction., Circulation., 93(2):356-64.,   1996年
  • Role of activation of protein kinase C in the infarct size-limiting effect of ischemic preconditioning through activation of ecto-5'-nucleotidase., Circulation., 93(4):781-91.,   1996年
  • Role of activation of ectosolic 5'-nucleotidase in the cardioprotection mediated by opening of K+c channels., Am J Physiol., 270(5 Pt 2):H1744-56,   1996年
  • Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs., J Am Coll Cardiol, 27(7):1804-12,   1996年
  • Activated polymorphonuclear leukocytes induce constriction of canine coronary artery via Mac-1, but not LFA-1, and ICAM-1., J Mol Cell Cardiol.,   1996年
  • Activation of ecto-5'-nucleotidase by protein kinase C attenuates irreversible cellular injury due to hypoxia and reoxygenation in rat cardiomyocytes., J Mol Cell Cardiol., 28(9):1945-55.,   1996年
  • Presence of poorly stained myocytes in acute myocarditis predicts improvement in cardiac function., J Cardiol., 28(4):213-20.,   1996年
  • Adenosine inhibits leukocyte-induced vasoconstriction., Am J Physiol, 271(6 Pt 2):H2622-8.,   1996年
  • Cardioprotection due to preconditioning correlates with increased ecto-5'-nucleotidase activity., Am J Physiol., 270(1 Pt 2):H238-44,   1996年
  • Activation of ecto-5'-nucleotidase and cardioprotection by ischemic preconditioning., Basic Res Cardiol., 91(1):23-6,   1996年
  • Increased release of NO during ischemia reduces myocardial contractility and improves metabolic dysfunction., Circulation., 93(2):356-64.,   1996年
  • Role of activation of protein kinase C in the infarct size-limiting effect of ischemic preconditioning through activation of ecto-5'-nucleotidase., Circulation., 93(4):781-91.,   1996年
  • Role of activation of ectosolic 5'-nucleotidase in the cardioprotection mediated by opening of K+c channels., Am J Physiol., 270(5 Pt 2):H1744-56,   1996年
  • Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs., J Am Coll Cardiol, 27(7):1804-12,   1996年
  • Activated polymorphonuclear leukocytes induce constriction of canine coronary artery via Mac-1, but not LFA-1, and ICAM-1., J Mol Cell Cardiol.,   1996年
  • Activation of ecto-5'-nucleotidase by protein kinase C attenuates irreversible cellular injury due to hypoxia and reoxygenation in rat cardiomyocytes., J Mol Cell Cardiol., 28(9):1945-55.,   1996年
  • Presence of poorly stained myocytes in acute myocarditis predicts improvement in cardiac function., J Cardiol., 28(4):213-20.,   1996年
  • Adenosine inhibits leukocyte-induced vasoconstriction., Am J Physiol, 271(6 Pt 2):H2622-8.,   1996年
  • Alpha 1-adrenoceptor activation increases ecto-5'-nucleotidase activity and adenosine release in rat cardiomyocytes by activating protein kinase C., Circulation., 91(8):2226-34,   1995年
  • Plasma nitric oxide end products are increased in the ischemic canine heart., Biochem Biophys Res Commun, 211(2):370-4.,   1995年
  • Beneficial effects of inhibition of angiotensin-converting enzyme on ischemic myocardium during coronary hypoperfusion in dogs., Circulation., 92(4):950-61.,   1995年
  • Bidirectional effects of aminophylline on myocardial ischemia., Circulation., 92(4):950-61.,   1995年
  • Downward shift of coronary pressure-flow relationship following a brief period of ischemia in dogs., Am J Physiol., 269(4 Pt 2):H1237-45,   1995年
  • Evidence for nitric oxide generation in the cardiomyocytes: its augmentation by hypoxia., J Mol Cell Cardiol, 27(10):2149-54,   1995年
  • Cardioprotection due to preconditioning correlates with increased ecto-5'-nucleotidase activity., Arterioscler Thromb Vasc Biol., 15(12):2298-304,   1995年
  • Alpha 1-adrenoceptor activation increases ecto-5'-nucleotidase activity and adenosine release in rat cardiomyocytes by activating protein kinase C., Circulation., 91(8):2226-34,   1995年
  • Plasma nitric oxide end products are increased in the ischemic canine heart., Biochem Biophys Res Commun, 211(2):370-4.,   1995年
  • Beneficial effects of inhibition of angiotensin-converting enzyme on ischemic myocardium during coronary hypoperfusion in dogs., Circulation., 92(4):950-61.,   1995年
  • Bidirectional effects of aminophylline on myocardial ischemia., Circulation., 92(4):950-61.,   1995年
  • Downward shift of coronary pressure-flow relationship following a brief period of ischemia in dogs., Am J Physiol., 269(4 Pt 2):H1237-45,   1995年
  • Evidence for nitric oxide generation in the cardiomyocytes: its augmentation by hypoxia., J Mol Cell Cardiol, 27(10):2149-54,   1995年
  • Cardioprotection due to preconditioning correlates with increased ecto-5'-nucleotidase activity., Arterioscler Thromb Vasc Biol., 15(12):2298-304,   1995年
  • 心筋虚血・再灌流障害に関する物質 (1)アデノシン, ”心筋虚血再灌流障害”(世界保健通信社),   1994年
  • Ischemic Preconditioning, Annual Review 循環器,   1994年
  • Infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of 5'-nucleotidase activity and attenuation of adenosine release., Circulation., 89(3):1237-46,   1994年
  • Alpha 1-adrenoceptor activation mediates the infarct size-limiting effect of ischemic preconditioning through augmentation of 5'-nucleotidase activity., J Clin Invest., 93(5):2197-205.,   1994年
  • AICA riboside improves myocardial ischemia in coronary microembolization in dogs., Am J Physiol.,   1994年
  • Infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of 5'-nucleotidase activity and attenuation of adenosine release., Circulation., 89(3):1237-46,   1994年
  • Alpha 1-adrenoceptor activation mediates the infarct size-limiting effect of ischemic preconditioning through augmentation of 5'-nucleotidase activity., J Clin Invest., 93(5):2197-205.,   1994年
  • AICA riboside improves myocardial ischemia in coronary microembolization in dogs., Am J Physiol.,   1994年
  • Which subgroup of patients with dilated cardiomyopathy would benefit from long-term beta-blocker therapy? A histologic viewpoint., J Am Coll Cardiol., 21(3):628-33.,   1993年
  • Superoxide dismutase enhances both adenosine release and coronary hyperemic flow through protection of 5'-nucleotidase against its degradation during reperfusion following ischemia in dogs., Biorheology., 359-70,   1993年
  • Attenuation of ecto-5'-nucleotidase activity and adenosine release in activated human polymorphonuclear leukocytes., Circ Res., 73(3):524-33,   1993年
  • Which subgroup of patients with dilated cardiomyopathy would benefit from long-term beta-blocker therapy? A histologic viewpoint., J Am Coll Cardiol., 21(3):628-33.,   1993年
  • Superoxide dismutase enhances both adenosine release and coronary hyperemic flow through protection of 5'-nucleotidase against its degradation during reperfusion following ischemia in dogs., Biorheology., 359-70,   1993年
  • Attenuation of ecto-5'-nucleotidase activity and adenosine release in activated human polymorphonuclear leukocytes., Circ Res., 73(3):524-33,   1993年
  • Characteristics of frequency content of atrial signal-averaged electrocardiograms during sinus rhythm in patients with paroxysmal atrial fibrillation., J Am Coll Cardiol., 19(3):559-63,   1992年
  • Dynamic process between the clotting and the lytic activities on intracardiac thrombi--its relationship with systemic embolization., Jpn Circ J., 56(8):793-800,   1992年
  • Characteristics of frequency content of atrial signal-averaged electrocardiograms during sinus rhythm in patients with paroxysmal atrial fibrillation., J Am Coll Cardiol., 19(3):559-63,   1992年
  • Dynamic process between the clotting and the lytic activities on intracardiac thrombi--its relationship with systemic embolization., Jpn Circ J., 56(8):793-800,   1992年
  • Detection of patients at risk for paroxysmal atrial fibrillation during sinus rhythm by P wave-triggered signal-averaged electrocardiogram., Circulation., 83(1):162-9,   1991年
  • Effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy--echocardiographical follow-up., Cardiovasc Drugs Ther., 5(2):463-9,   1991年
  • Detection of patients at risk for paroxysmal atrial fibrillation during sinus rhythm by P wave-triggered signal-averaged electrocardiogram., Circulation., 83(1):162-9,   1991年
  • Effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy--echocardiographical follow-up., Cardiovasc Drugs Ther., 5(2):463-9,   1991年
  • Human Atrial Natriuretic Peptide and Nicorandil as an Adjunct to Reperfusion Therapy for Acute Myocardial Infarction with ST-segment Elevation: the Randomised J-WIND (Japan-Working Groups of Acute Myocardial Infarction for the Reduction of Necrotic Dam・・・, Lancet
    Human Atrial Natriuretic Peptide and Nicorandil as an Adjunct to Reperfusion Therapy for Acute Myocardial Infarction with ST-segment Elevation: the Randomised J-WIND (Japan-Working Groups of Acute Myocardial Infarction for the Reduction of Necrotic Damage) Trials

書籍等出版物

  • 医学のあゆみ<心不全-研究と臨床の最前線> 小胞体ストレスと心不全, 医歯薬出版株式会社,   2010年
  • DDSの現状-循環器領域でのDDS, メディカルレビュー社,   2009年
  • 心不全発症のメカニズム<蛋白質の品質管理と心筋機能維持>, 北隆館,   2009年
  • 心不全発症のメカニズム<蛋白質の品質管理と心筋機能維持>, BIO CLNICA,   2009年
  • リポソームを用いた急性心筋梗塞に対する新しい薬物治療法の開発, Drug Delivery System,   2009年
  • プラークバイオロジーの新展開:急性冠症候群の分子イメージングとナノ治療, 先端医学社,   2009年
  • 心房リモデリング, 診断と治療(診断と治療社),   2009年
  • 新・心臓病診療プラクティス 12 冠動脈疾患の病態に迫る <再灌流障害に迫る>, 文光堂,   2008年
  • エリスロポエチンによる心筋梗塞後リモデリング抑制の機序, 第4回心血管再生医療フォーラム(先端医療振興財団),   2007年
  • 循環器医の糖尿病治療2007, Diabetes & Cardiovascular Disease,   2007年
  • <Integrated Medicineとしての循環器病学> 心臓リモデリングにおける小胞体ストレスの役割, メディカルレビュー社,   2007年
  • <Integrated Medicineとしての循環器病学> サイトカインによる心筋虚血再灌流障害抑制効果, メディカルレビュー社,   2007年
  • 蛋白品質管理機構と心血管リモデリング, クリニシャン,   2007年
  • 慢性心不全の地域連携<心不全におけるワーファリン治療>, 治療,   2007年
  • 急性冠症候群におけるRAS阻害, 内科,   2007年
  • 小胞体ストレスと心血管疾患, Medical Science Digest,   2007年
  • 活性酵素と小胞体ストレス, Cardiac Practice,   2007年
  • 第4回心血管再生医療フォーラム エリスロポエチンによる心筋梗塞後リモデリング抑制の機序, 先端医療振興財団,   2007年
  • 不全心における小胞体ストレス., 医学のあゆみ,   2006年
  • 心臓における小胞体ストレス, LiSA,   2005年
  • 急性心筋梗塞の大規模臨床試験:J-WIND, 救急・集中治療,   2004年
  • スタチン系薬剤と他剤との併用による循環器疾患への治療効果, メディカルレビュー社,   2003年
  • 心房細動でなぜ血栓ができるのか, Heart View,   2001年
  • 心房細動におけるNO低下とその機序, "心房細動・粗動・頻拍"(医学書院),   1999年
  • セレクチン, 細胞工学別冊:動脈硬化+高脂血症研究ストラテジー,   1996年

講演・口頭発表等

  • ドラッグデリバリーシステムを用いた急性心筋梗塞治療薬の開, 公益社団法人 日本薬剤学会第31年会,   2016年
  • A Chemical Endoplasmie Reticulum Chaperone Attenuates Cardiac Dysfunction by Doxorubicin, Biology,Chemistry,and Therapeutic Applications of Nitric Oxide,   2016年

作品

  • 日本循環器学会TR振興事業,   2010年
  • ラット心筋梗塞モデルにおける化合物の心機能及びリモデリングに対する作用検討,   2010年
  • 急性心筋梗塞患者における血中エリスロポエチン濃度と血管内皮前駆細胞数・慢性期梗塞領域血流量の関連の検討,   2010年
  • 20050101:創薬基盤推進研究事業 "大規模発現解析より得られた新規酵素心臓特異的ミオシン軽鎖キナーゼ(cardiacMLCK)を利用した心不全治療薬・診断マーカーの開発(H20-ゲノム-一般-004),   2009年
  • 心筋細胞の非分裂性を規定する因子の同定・機能解析と治療への応用に向けた基盤研究(20-22年度),   2009年
  • 共同研究の題目:急性心筋梗塞患者における血中エリスロポエチン濃度と血管内皮前駆細胞数・慢性期梗塞領域血流量の関連の検討,   2009年
  • 難治性疾患克服研究事業:重症特発性心筋症患者の生体資料の収集及び新規予後規定因子の検索・解析 (H21-難治ー一般ー089),   2009年
  • ナノサイズリポソームを用いた急性心筋梗塞治療法の開発,   2009年
  • 大規模発現解析より得られた新規酵素心臓特異的ミオシン軽鎖キナーゼ(cardiacMLCK)を利用した心不全治療薬・診断マーカーの開発(H20-ゲノム-一般-004),   2008年
  • 共同研究の題目:急性心筋梗塞患者における血中エリスロポエチン濃度と血管内皮前駆細胞数・慢性期梗塞領域血流量の関連の検討,   2008年
  • 心筋細胞の非分裂性を規定する因子の同定・機能解析と治療への応用に向けた基盤研究(20-22年度),   2008年
  • 心血管リモデリングにおける小胞体-ユビキチン・プロテアソーム系の役割の解明,   2008年
  • ナノサイズリポソームを用いた急性心筋梗塞治療法の開発,   2008年
  • 共同研究の題目:急性心筋梗塞患者における血中エリスロポエチン濃度と血管内皮前駆細胞数・慢性期梗塞領域血流量の関連の検討,   2007年
  • ナノサイズリポソームを用いた急性心筋梗塞治療法の開発,   2007年
  • 心血管リモデリングにおける小胞体-ユビキチン・プロテアソーム系の役割の解明,   2007年
  • 心不全進展における小胞体-ユビキチン・プロテアソーム系の役割の解明,   2006年
  • 慢性心不全に対する在宅酸素療法の長期比較臨床試験,   2006年
  • 急性心筋梗塞患者における血中エリスロポエチン濃度と血管内皮前駆細胞数・慢性期梗塞領域血流量の関連の検討,   2006年
  • リポソームを用いた新たな急性心筋梗塞治療法の開発,   2006年
  • 小胞体ストレスシグナルCHOP測定キットの開発,   2005年
  • 心不全進展における小胞体-ユビキチン・プロテアソーム系の役割の解明,   2005年
  • シンビット注使用成績調査,   2004年
  • 心房細動における心房筋の電気的・構造的リモデリングに関する分子生理学的検討,   2003年
  • 心房細動における心房筋の電気的・構造的リモデリングに関する分子生理学的検討,   2002年
  • 心房細動における心房筋の電気的・構造的リモデリングに関する分子生理学的検討,   2001年
  • 心房細動におけるNO・アデノシンの役割-脳血栓塞栓症発生機序の新しい概念,   1998年
  • 心房細動におけるNO・アデノシンの役割-脳血栓塞栓症発生機序の新しい概念,   1997年
  • 内皮由来一酸化窒素が蛋白合成に中心的役割を果たすp70 S6kinase におよぼす影響,   1997年
  • 心筋虚血耐性獲得におけるアデノシン産生酵素活性化の意義とその分子機構の解明,   1996年

特許

  • 細胞融合促進剤、およびその使用 (アメリカ), US7,897,397
  • 細胞融合促進剤、及びその使用 欧州特許証 (欧州), 1792985
  • 細胞融合促進剤、及びその使用, 特許4294688号
  • 心筋梗塞の予防および/または治療法, PCT/JP2008/00652
  • 心筋の小胞体ストレス抑制剤, 特願2007-247227
  • 心筋梗塞の予防および/または治療法, 特願2007-073016
  • 細胞融合促進剤、及びその使用 (アメリカ), WO 2006/011354 A1
  • 心筋組織の障害を抑制するための医薬組成物, 特願2005-040930
  • 心不全の判定方法, 特願2005-272336
  • METHOD FOR DIAGONSING HEART FAILURE (アメリカ), 548019
  • METHOD FOR DIAGONSING HEART FAILURE (America)
  • CELL FUSION POMOTER AND UTILIZATION OF THE SAME (America), WO 2006/011354 A1
  • METHOD FOR DIAGONSING HEART FAILURE (America), 548019

受賞

  •   2009年, 若手研究実用化チャレンジ・優秀賞
  •   2007年, 協和メディックス 第一回診断薬シーズ・コンテスト優秀賞
  •   2005年, 協和メディックス 第一回診断薬シーズ・コンテスト優秀賞
  •   2004年, 米国心臓協会(AHA)Outstanding Early Career Investigator Awards
  •   2004年, Outstanding Early Career Investigator Awards
  •   1999年, 米国心臓協会(AHA)Melvin Marcus Young Investigator Award
  •   1999年, Melvin Marcus Young Investigator Awards of American Heart Association
  •   1998年, 日本心臓財団・分子循環器研究助成優秀賞
  •   1998年, 日本心臓財団・分子循環器研究助成優秀賞
  •   1998年, 日本心臓病学会Young Investigator Award
  •   1998年, Finalist of Young Investigator Awards of Japanese College of Cardiology
  •   1997年, 日本心臓財団・ファイザー心血管病研究助成優秀賞
  •   1997年, 内藤医学研究振興財団海外留学費助成優秀賞
  •   1997年, 日本心臓財団・ファイザー心血管病研究助成優秀賞

競争的資金

  • 心房細動検出機器開発,   2017年
  • 抗体薬物複合体による不安定プラークの画像診断・治療の一体化開発,   2015年
  • 心房細動における脳卒中発症のメカニズム解明と治療法の開発
  • 心血管リモデリングにおける蛋白品質管理機構
  • ナノテクノロジーを用いた心筋梗塞治療法の開発
  • -
  • 小児生活習慣病予防健診を活用したFHリバーススクリーニング制度の確立