Elucidation of molecular mechanisms underlying cell death in heart failure

• Project/Area Number: 19390214
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Osaka University
• Principal Investigator: OTSU Kinya Osaka University, 医学系研究科, 准教授 (20294051)
• Co-Investigator(Kenkyū-buntansha): NISHIDA Kazuhiko 大阪大学, 歯学研究科, 助教 (90362681) ; HIKOSO Shungo 大阪大学, 保健センター, 助教 (30423164)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 心不全 / 細胞死 / ネクローシス / アポトーシス / オートファジー

Research Abstract

慢性心不全の発症・進展においては細胞死が重要な働きをしている。各種神経体液因子で活性化されるMAPKKKの一種であるASK1の活性化が心筋細胞アポトーシスの惹起に重要であり、下流のキナーゼであるJNK非依存性に関わっていることを見出した。ネクローシスも心不全の発症に関わっていることを明らかにした。さらにオートファジーは細胞死に関わるのではなく外的ストレスに対し細胞保護的に働いていることが明らかにした。

Research Products

• [Journal Article] Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes (2009)
  • Author(s): Shigemiki Omiya, Shungo Hikoso, Yukiko Imanishi, Atsuhiro Saito, Osamu Yamaguchi, Toshihiro Takeda, Isamu Mizote, Takafumi Oka, Manabu Taneike, Yuko Nakano, Yasushi Matsumura, Kazuhiko Nishida, Yoshiki Sawa, Masatsugu Hori, Kinya Otsu
  • Journal Title: J. Mol. Cell. Cardiol 46 Pages: 59-66
  • Peer Reviewed
• [Journal Article] Apoptosis signal-regulating kinase 1(ASK1)/p38 signaling pathway negatively regulates physiological hypertrophy (2008)
  • Author(s): Masayuki Taniike, Osamu Yamaguchi, Ikuko Tsujimoto, Shungo Hikoso, Toshihiro Takeda, Atsuko Nakai, Shigemiki Omiya, Isamu Mizote, Yuko Nakano, Yoshiharu Higuchi, Yasushi Matsumura, Kazuhiro Nishida, Masatsugu Hori, Hidenori Ichijo, Kinya Otsu
  • Journal Title: Circulation 117 Pages: 545-552
  • Peer Reviewed
• [Journal Article] Reduction in hemoglobin-oxygen affinity results in the improvement of exercise capacity in mice with chronic heart failure (2008)
  • Author(s): Tetsuya Watanabe, Toshihiro Takeda, Shigemiki Omiya, Shungo Hikoso, Osamu Yamaguchi, Yuko Nakano, Yoshiharu Higuchi, Atsuko Nakai, Yusuke Abe, Yayoi Aki-Jin, PhD, Masayuki Taniike, Isamu Mizote, Yasushi Matsumura, Takahiko Shimizu, Kazuhiko Nishida, Kiyohiro Imai, Masatsugu Hori, Takuji Shirasawa, Kinya Otsu
  • Journal Title: J. Am. Coll. Cardiol. 52 Pages: 779-786
  • Peer Reviewed
• [Journal Article] Downregulation of territin heavy chain increases labile iron pool, Oxidative stress and cell death in cardiomyocytes (2008)
  • Author(s): Shigemiki Omiya, 他
  • Journal Title: Journal of Molecular and Cellular Cardiology 46 Pages: 59-66
  • Peer Reviewed
• [Journal Article] Apoptosis signal-regulating kinase 1 (ASK1)/p38 signaling pathway negatively regulates physiological hypertrophy (2008)
  • Author(s): Masayuki Taniike, 他
  • Journal Title: Circulation 117 Pages: 545-552
  • Peer Reviewed
• [Journal Article] Reduction in hemoglobin-oxygen affinity results in the improvement ofexercise capacity in mice with chronic heart failure (2008)
  • Author(s): Tetsuya Watanabe, 他
  • Journal Title: Journal of American College of Cardiology 52 Pages: 779-786
  • Peer Reviewed
• [Journal Article] The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress (2007)
  • Author(s): Atsuko Nakai, Osamu Yamaguchi, Toshihiro Takeda, Yoshiharu Higuchi, Shungo Hikoso, Masayuki Taniike, Shigemiki Omiya, Isamu Mizote, Yasushi Matsumura, Michio Asahi, Kazuhiko Nishida, Masatsugu Hori, Noboru Mizushima, Kinya Otsu
  • Journal Title: Nature Medicine 13 Pages: 619-624
  • Peer Reviewed
• [Journal Article] Progression of heart failure was suppressed by inhibition of apoptosis signal-regulating kinase 1 via transcoronary gene transfer (2007)
  • Author(s): Shungo Hikoso, Yasuhiro Ikeda, Osamu Yamaguchi, Toshihiro Takeda, Yoshiharu Higuchi, Shinichi Hirotani, Kazunori Kashiwase, Michio Yamada, Michio Asahi, Yasushi Matsumura, Kazuhiko Nishida, Masunori Matsuzaki, Masatsugu Hori, Kinya Otsu
  • Journal Title: J. Am. Coll. Cardiol 50 Pages: 453-462
  • Peer Reviewed
• [Journal Article] The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress (2007)
  • Author(s): Nakai A, et. al.
  • Journal Title: Nature Medicine 13 Pages: 619-624
  • Peer Reviewed
• [Journal Article] Progression of Heart Failure was Suppressed by Inhibition of Apoptosis Signal-regulating Kinase 1 (ASK1) via Transcoronary Gene Transfer (2007)
  • Author(s): Hikoso, et. al.
  • Journal Title: J. Am. Coll. Cardiol. 50 Pages: 453-462
  • Peer Reviewed
• [Journal Article] Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling (2007) (2007)
  • Author(s): Nakaoka Y, et.al.
  • Journal Title: J. Clin. Invest. 117 Pages: 1771-1781
  • Peer Reviewed
• [Presentation] Non-apoptotic cardiomyocyte death as a cause of cardiac remodeling (2009)
  • Author(s): Osamu Yamaguchi
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2009-03-22
• [Presentation] Cardiac-specific disruption of calpain4 revealed its cardioprotective role in response to pressure overload (2009)
  • Author(s): Isamu Mizote
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2009-03-21
• [Presentation] Constitutive autophagy is required to maintain cardiac structure and function in aged mouse hearts (2009)
  • Author(s): Manabu Taneike
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2009-03-21
• [Presentation] Role of autophagy in heart failure (2009)
  • Author(s): Kinya Otsu
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2009-03-20
• [Presentation] Altered Autophagy in Cardiomyopathy (2008)
  • Author(s): Kinya Otsu
  • Organizer: European Society of Cardiology, Heart Failure
  • Place of Presentation: Milano, Italy
  • Year and Date: 2008-06-14
• [Presentation] Altered Autophagy in Cardiomyopathy (2008)
  • Author(s): 大津欣也
  • Organizer: European Society of Cardiology, Heart Failure
  • Place of Presentation: イタリア、ミラノ
  • Year and Date: 2008-06-14
• [Presentation] IKKb/NF-kB pathway protects hearts from hemodynamic stress medicated through regulation of MnSOD expression (2008)
  • Author(s): Shungo Hikoso
  • Organizer: The 72nd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2008-03-29
• [Presentation] Cross-talk between p38 dependent pathological remodeling cascade and cardiac adaptive responses (2008)
  • Author(s): Masayuki Taniike
  • Organizer: The 72nd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2008-03-29
• [Presentation] Downregulation of ferritin heavy chain is an important trigger of cardiac cell death and progression of heart failure (2008)
  • Author(s): Shigemiki Omiya
  • Organizer: The 72nd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2008-03-28
• [Presentation] IKKb/NF-kB pathway protects hearts from hemodynamic stress medicated through regulation of MnSOD expression (2007)
  • Author(s): Shungo Hikoso
  • Organizer: Scientific Sessions, American Heart Association
  • Place of Presentation: Orland, USA
  • Year and Date: 2007-11-07
• [Presentation] Cardiac-specific activation of apoptosis signal-regulating kinase 1 leads to cardiac dysfunction with pathological hypertrophy (2007)
  • Author(s): Toshihiko Takeda
  • Organizer: Scientific Sessions, American Heart Association
  • Place of Presentation: Orland, USA
  • Year and Date: 2007-11-04
• [Presentation] Ablation of apoptosis signal-regulating kinase improves cardiac stress-resistance (2007)
  • Author(s): Otsu, K
  • Organizer: European Society of Cardiology, Heart Failure
  • Place of Presentation: ハンブルグ、ドイツ
  • Year and Date: 2007-06-10