The investigation of the role of protein degradation pathway during progression to heart failure, and the application to heart failure treatment.

• Project/Area Number: 20790529
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Osaka University
• Principal Investigator: HIKOSO Shungo Osaka University, 保健センター, 助教 (30423164)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 分子心臓病態学 / 心不全 / 蛋白分解 / カルパイン / アポトーシス / タンパク分解系

Research Abstract

We investigated the role of calpain pathway which is known as a protein degradation pathway in the pathogenesis of heart failure using cardiac-specific calpain4-deficient mice. We found the increase in apoptotic cardiomyocyte death in deficient mice in response to pressure overload, leading to cardiac dilatation and decreased cardiac contractility. Thus, we concluded that calpain pathway in the heart plays a protective role in response to pressure overload mediated through the inhibition of stress-induced cardiomyocyte apoptosis.

Research Products

• [Journal Article] Activation of MTK1/MEKK4 induces cardiomyocyte death and heart failure (2010)
  • Author(s): I Mizote, O Yamaguchi, S Hikoso, T Takeda, M Taneike, T Oka, T Tamai, J Oyabu, Y Matsumura, K Nishida, I Komuro, M Hori, K Otsu
  • Journal Title: Journal of Molecular and Cellular Cardiology 48 Pages: 302-209
  • Peer Reviewed
• [Journal Article] Activation of MTK1/MEKK4 induces cardiomyocyte death and heart failure (2010)
  • Author(s): Isamu Mizote, 他
  • Journal Title: Journal of Molecular and Cellular Cardiology 48 Pages: 302-309
  • Peer Reviewed
• [Journal Article] The I B kinase /NF- B signaling pathway protects the heart from hemodynamic stress mediated by the regulation of MnSOD expression (2009)
  • Author(s): S Hikoso, O Yamaguchi, Y Nakano, T Takeda, S Omiya, I Mizote, M Taneike, T Oka, T Tamai, J Oyabu, Y Uno, Y Matsumura, K Nishida, K Suzuki, M Kogo, M Hori, K Otsu
  • Journal Title: Circulation Research 105 Pages: 70-79
  • Peer Reviewed
• [Journal Article] Cardiac steroidogenesis and glucocorticoid in the development of cardiac hypertrophy during the proression to heart failure (2009)
  • Author(s): T Ohtani, T Mano, S Hikoso, Y Sakata, M Nishio, Y Takeda, K Otsu, T Miwa, T Masuyama, M Hori, K Yamamoto
  • Journal Title: Journal of Hypertensions 27 Pages: 1074-1083
  • Peer Reviewed
• [Journal Article] Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes (2009)
  • Author(s): S Omiya, S Hikoso, Y Imanishi, A Saito, O Yamaguchi, T Takeda, I Mizote, T Oka, M Taniike, Y Nakano, Y Matsumura, K Nishida, Y Sawa, M Hori, K Otsu
  • Journal Title: Journal of Molecular and Cellular Cardiology 46 Pages: 59-66
  • Peer Reviewed
• [Journal Article] The IκB kinase β/NF-κB signaling pathway protects the heart from hemodynamic stress mediated by the regulation of MnSOD expression (2009)
  • Author(s): Shungo Hikoso, 他
  • Journal Title: Circulation Research 105 Pages: 70-79
  • Peer Reviewed
• [Journal Article] Cardiac steroidogenesis and glucocorticoid in the development of cardiac hypertrophy during the proression to heart failure (2009)
  • Author(s): T Ohtani, 他
  • Journal Title: Journal of Hypertensions 27 Pages: 1074-1083
  • 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): T Watanabe, T Takeda, S Omiya, S Hikoso, O Yamaguchi, Y Nakano, Y Higuchi, A Nakai, Y Abe, Y Aki-Jin, M Taniike, I Mizote, Y Matsumura, T Shimizu, K Nishida, K Imai, M Hori, T Shirasawa, K Otsu
  • Journal Title: Journal of the American College of Cardiology 52 Pages: 779-786
  • Peer Reviewed
• [Journal Article] Apoptosis signal-regulating kinase 1/p38 signaling pathway negatively regulates physiological hypertrophy (2008)
  • Author(s): M Taniike, O Yamaguchi, I Tsujimoto, S Hikoso, T Takeda, A Nakai, S Omiya, I Mizote, Y Nakano, Y Higuchi, Y Matsumura, K Nishida, H Ichijo, M Hori, K Otsu
  • Journal Title: Circulation 117 Pages: 545-52
  • Peer Reviewed
• [Journal Article] Downregulation of ferritin 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
• [Presentation] The in Vivo Role of IκB kinase β(IKKβ)/NF-κB Signalling Pathway in the Heart. (2009)
  • Author(s): 彦惣俊吾
  • Organizer: 国際心臓研究学会日本部会総会
  • Place of Presentation: 札幌市
  • Year and Date: 2009-12-04
• [Presentation] 心筋細胞においてフェリチン重鎖の減少は遊離鉄および酸化ストレスの増加をもたらし細胞死を誘導する (2009)
  • Author(s): 大宮茂幹、彦惣俊吾、大津欣也
  • Organizer: 第19回日本循環薬理学会
  • Place of Presentation: 京都
  • Year and Date: 2009-11-27
• [Presentation] The in vivo Role of IKK /NF- B Signaling Pathway in the Heart (2009)
  • Author(s): 彦惣俊吾、大津欣也、小室一成、堀正二
  • Organizer: 第26回国際心臓研究学会日本部会
  • Place of Presentation: 札幌
• [Presentation] I B Kinase /NF- B Pathway Protects Hearts from Hemodynamic Stress Mediated through Regulating Manganese Superoxide Dismutase Expression (2009)
  • Author(s): S Hikoso, O Yamaguchi, T Takeda, S Omiya, K Suzuki, K Nishida, M Karin, K Otsu
  • Organizer: The 36th Congress of the International Union of Physiological Science
  • Place of Presentation: Kyoto, Japan
• [Presentation] The I B kinase (IKK /NF- B signaling pathway protects the heart in response to hemodynamic stress (2009)
  • Author(s): 彦惣俊吾、大津欣也、堀正二
  • Organizer: 第32回心筋代謝研究会
  • Place of Presentation: 大阪
• [Presentation] Cardiac-specific Disruption of Calpain4 Revealed Its Cardioprotective Role in Response to Pressure Overload (2009)
  • Author(s): 溝手勇、山口修、彦惣俊吾、武田理宏、大宮茂幹、松村泰志、西田和彦、堀正二、大津欣也
  • Organizer: 第73回日本循環器学会学術集会
  • Place of Presentation: 大阪
• [Presentation] Constitutive autophagy is required to maintain cardiac structure and function in aged mouse hearts (2009)
  • Author(s): 種池学、山口修、中井敦子、彦惣俊吾、武田理宏、大宮茂幹、西田和彦、堀正二、水島昇、大津欣也
  • Organizer: 第73回日本循環器学会学術集会
  • Place of Presentation: 大阪
• [Presentation] The role of IKKβ/NF-κB pathway in the pathogenesis of heart failure (2008)
  • Author(s): 彦惣俊吾, 他
  • Organizer: 第25回国際心臓研究会日本部会
  • Place of Presentation: 横浜
  • Year and Date: 2008-12-06
• [Presentation] IκB kinase ss (IKKss)/NF-κB signaling pathway protects hearts from hemodynamic stress mediated through regulating MnSOD expression (2008)
  • Author(s): 彦惣俊吾, 他
  • Organizer: 第72回日本循環器学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2008-03-29
• [Presentation] Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes (2008)
  • Author(s): 大宮茂幹、彦惣俊吾、大津欣也
  • Organizer: 第25回国際心臓研究学会日本部会
  • Place of Presentation: 横浜
• [Presentation] The role of IKK /NF- B pathway in the pathogenesis of heart failure (2008)
  • Author(s): 彦惣俊吾、山口修、堀正二、大津欣也
  • Organizer: 第25回国際心臓研究学会日本部会
  • Place of Presentation: 横浜
• [Presentation] Cardiac-specific Activation of Apoptosis Signal-regulating Kinase 1 Leads to Cardiac Dysfunction with Pathological Hypertrophy (2008)
  • Author(s): 武田理宏、大津欣也、山口修、廣谷信一、彦惣俊吾、樋口義治、谷池正行、中井敦子、大宮茂幹、種池学、岡崇史、西田和彦、堀正二
  • Organizer: American Heart Assocoation Scientific Sessions 2008
  • Place of Presentation: アメリカ合衆国、ニューオーリンズ