Role of protein homeostasis in cardiac aging

• Project/Area Number: 21590928
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto University
• Principal Investigator: SHIOI Tetsuo 京都大学, 医学研究科, 講師 (50360095)
• Co-Investigator(Kenkyū-buntansha): KONDOH Hiroshi 京都大学, 医学研究科, 助教 (80402890)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 分子心臓病態学 / 心不全 / エネルギー代謝 / ミトコンドリア / SIRT1 / 代謝 / 老化 / メタボローム / ジクロロアセテート / ラパマイシン

Research Abstract

Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging. We analyzed age-associated changes in murine heart and the manner in which suppression of the p110-alpha isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart. In conclusion, suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.

Research Products

• [Journal Article] Effect of persistent activation of phosphoinositide 3-kinase on heart (2012)
  • Author(s): Niizuma S, Inuzuka Y, Okuda J, Kato T, Kawashima T, Tamaki Y, Iwanaga Y, Yoshida Y, Kosugi R, Watanabe-Maeda K, Machida Y, Tsuji S, Aburatani H, Izumi T, Kita T, Kimura T, Shioi T.
  • Journal Title: Life Sci Volume: 90 Issue: 15-16 Pages: 619-628
  • DOI: 10.1016/j.lfs.2012.02.010
  • Peer Reviewed
• [Journal Article] Analysis of liver metabolism in a rat model of heart failure (2011)
  • Author(s): Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Kawamoto A, Tamaki Y, Iwanaga Y, Soga T, Kita T, Kimura T, Shioi T.
  • Journal Title: Int J Cardiol Volume: (In press) Issue: 3 Pages: 130-136
  • DOI: 10.1016/j.ijcard.2011.07.056
  • Peer Reviewed
• [Journal Article] Constitutive SIRT1 Overexpression Impairs Mitochondria and Reduces Cardiac Function in Mice (2011)
  • Author(s): Tsuneaki Kawashima, et al
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 51 Issue: 6 Pages: 1026-1036
  • DOI: 10.1016/j.yjmcc.2011.09.013
  • Peer Reviewed
• [Journal Article] Analysis of Metabolic Remodeling in Compensated Left Ventricular Hypertrophy and Heart Failure (2010)
  • Author(s): Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, Iwanaga Y, Narazaki M, Matsuda T, Soga T, Kita T, Kimura T, Shioi T.
  • Journal Title: Circ Heart Fail Volume: 3 Pages: 420-30
  • Peer Reviewed
• [Journal Article] PI3K(p110alpha) protects against myocardial infarction-induced heart failure : identification of PI3K-regulated miRNA and mRNA (2010)
  • Author(s): Lin RC, Weeks KL, Gao XM, Williams RB, Bernardo BC, Kiriazis H, Matthews VB, Woodcock EA, Bouwman RD, Mollica JP, Speirs HJ, Dawes IW, Daly RJ, Shioi T, Izumo S, Febbraio MA, Du XJ, McMullen JR.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 4 Pages: 724-732
  • Peer Reviewed
• [Journal Article] Analysis of Metabolic Remodeling in Compensated Left Ventricular Hypertrophy and Heart Failure. (2010)
  • Author(s): Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, Iwanaga Y, Narazaki M, Matsuda T, Soga T, Kita T, Kimura T, Shioi T.
  • Journal Title: Circ Heart Fail. Volume: 3 Pages: 420-430
  • Peer Reviewed
• [Journal Article] P13K (p110alpha) protects against myocardial infarction-induced heart failure : identification of PI3K-regulated miRNA and mRNA. (2010)
  • Author(s): Lin RC, Weeks KL, Gao XM, Williams RB, Bernardo BC, Kiriazis H, Matthews VB, Woodcock EA, Bouwman RD, Mollica JP, Speirs HJ, Dawes IW, Daly RJ, Shioi T, Izumo S, Febbraio MA, Du XJ, McMullen JR.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 4 Pages: 724-732
  • Peer Reviewed
• [Journal Article] Suppression of Phosphoinositide 3-kinase Prevents Cardiac Aging in Mice (2009)
  • Author(s): Inuzuka Y, Okuda J, Kawashima T, Kato T, Niizuma S, Tamaki Y, Iwanaga Y, Yoshida Y, Kosugi R, Watanabe-Maeda K, Machida Y, Tsuji S, Aburatani H, Izumi T, Kita T, Shioi T.
  • Journal Title: Circulation Volume: 120 Pages: 1695-1703
  • Peer Reviewed
• [Journal Article] Reduced Phosphoinositide 3-Kinase(p110{alpha}) Activation Increases the Susceptibility to Atrial Fibrillation (2009)
  • Author(s): Pretorius L, Du XJ, Woodcock EA, Kiriazis H, Lin RC, Marasco S, Medcalf RL, Ming Z, Head GA, Tan JW, Cemerlang N, Sadoshima J, Shioi T, Izumo S, Lukoshkova EV, Dart AM, Jennings GL, McMullen JR.
  • Journal Title: Am J Pathol Volume: 175 Pages: 998-1009
  • Peer Reviewed
• [Journal Article] Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase Cbeta2 in the regulation of physiologic developmental hypertrophy and heart function. (2009)
  • Author(s): Rigor DL, Bodyak N, Bae S, Choi JH, Zhang L, Ter-Ovanesyan D, He Z, McMullen JR, Shioi T, Izumo S, King GL, Kang PM.
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 296 Pages: 566-572
  • Peer Reviewed
• [Journal Article] Suppression of Phosphoinositide 3-kinase Prevents Cardiac Aging in Mice. (2009)
  • Author(s): Inuzaka Y, Okuda J, Kawashima T, Kato T, Niizuma S, Tamaki Y, Iwanaga Y, Yoshida Y, Kosugi R, Watanabe-Maeda K, Machida Y, Tsuji S, Aburatani H, Izumi T, Kita T, Shioi T.
  • Journal Title: Circulation 120 Pages: 1695-1703
  • Peer Reviewed
• [Journal Article] Reduced Phosphoinositide 3-Kinase (p110{alpha}) Activation Increases the Susceptibility to Atrial Fibrillation. (2009)
  • Author(s): Pretorius L, Du XJ, Woodcock EA, Kiriazis H, Lin RC, Marasco S, Medcalf RL, Ming Z, Head GA, Tan JW, Cemerlang N, Sadoshima J, Shioi T, Izumo S, Lukoshkova EV, Dart AM, Jennings GL, McMullen JR.
  • Journal Title: Am J Pathol. 175 Pages: 998-1009
  • Peer Reviewed
• [Journal Article] Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase Cbeta2 in the regulation of physiologic developmental hypertrophy and heart function. (2009)
  • Author(s): Rigor DL, Bodyak N, Bae S, Choi JH, Zhang L, Ter-Ovanesyan D, He Z, McMullen JR, Shioi T, Izumo S, King GL, Kang PM.
  • Journal Title: Am J Physiol Heart Circ Physiol. 296
  • Peer Reviewed
• [Presentation] Role of phosphoinositide 3-kinase in cardiac aging (2011)
  • Author(s): Shioi T.
  • Organizer: Ninth Annual Scientific Sessions, Society for Heart and Vascular Metabolism(招待講演)
  • Place of Presentation: Dolce La Hulpe Brussels(ブリュッセル,ベルギー)
  • Year and Date: 2011-06-18
• [Presentation] Role of phosphoinositide 3-kinase in cardiac aging (2011)
  • Author(s): Shioi T
  • Organizer: Ninth Annual Scientific Sessions, Society for Heart and Vascular Metabolism
  • Place of Presentation: ブリュッセル(ベルギー)(招待講演)
  • Year and Date: 2011-06-18
• [Presentation] Cardiac cachexia is associated with abnormal liver metabolism and pro-inflammatory responses in a rat model of heart failure (2011)
  • Author(s): Kato T, Shioi T, Niizuma S, Kawashima T, Okuda J, Kawamoto A, Tamaki Y, Iwanaga Y, Soga T, Kita T, Kimura T.
  • Organizer: Orange County Convention Center
  • Place of Presentation: Orange County Convention Center(Orlando, USA)
• [Presentation] Tc-99m sestamibi is a useful noninvasive method to assess cardiac mitochondrial function in vivo (2011)
  • Author(s): Kawamoto A, Shioi T, Kato T, Niizuma S, Kawashima T, Okuda J, Tanada Y, Tamaki Y, Kimura T.
  • Organizer: The 83th Scientific Sessions of American Heart Association
  • Place of Presentation: Orange County Convention Center(Orlando, USA)
• [Presentation] Cardiac cachexia is associated with abnormal liver metabolism and pro-inflammatory responses in a rat model of heart failure (2011)
  • Author(s): Kato T, Shioi T, Niizuma S, Kawashima T, Okuda J, Kawamoto A, Tamaki Y, Iwanaga Y, Soga T, Kita T, Kimura T
  • Organizer: The 83th Scientific Sessions of American Heart Association
  • Place of Presentation: オーランド(米国)
• [Presentation] Tc-99m sestamibi is a useful noninvasive method to assess cardiac mitochondrial function in vivo (2011)
  • Author(s): Kawamoto A, Shioi T, Kato T, Niizuma S, Kawashima T, Okuda J, Tanada Y, Tamaki Y, Kimura T
  • Organizer: The 83th Scientific Sessions of American Heart Association
  • Place of Presentation: オーランド(米国)
• [Presentation] Constitutive SIRT1 over expression impairs mitochondrial function in mice (2010)
  • Author(s): Kawashima T, Inuzuka Y, Okuda J, Kato T, Niizuma S, Tamaki Y, Narazaki M, Matsuda T, Adachi S, Takemura G, Kita T, Kimura T, Shioi T.
  • Organizer: The 82th Scientific Sessions of American Heart Association
  • Place of Presentation: Chicago(USA)
• [Presentation] A constitutive activation of phosphoinositide 3-kinase modifies cardiac aging in mice (2010)
  • Author(s): Niizuma S, Inuzuka Y, Okuda J, Kawashima T, Kato T, Tamaki Y, Kawamoto A, Iwanaga Y, Yoshida Y, Kosugi R, Watanabe-maeda K, Machida Y, Tsuji S, Aburatani H, Izumi T, Kita T, Kimura T, Shioi T.
  • Organizer: The 82th Scientific Sessions of American Heart Association
  • Place of Presentation: McCormick Place(Chicago, USA)
• [Presentation] Over expression of phosphoglycerate mutase, a glycolytic enzyme, induces proinflammatory response and impairs cardiac function. The 82th Scientific Sessions of American Heart Association (2010)
  • Author(s): Okuda J, Niizuma S, Kato T, Inuzuka Y, Kawashima T, Tamaki Y, Iwanaga Y, Kita T, Kimura T, Shioi T.
  • Organizer: The 82th Scientific Sessions of American Heart Association
  • Place of Presentation: McCormick Place(Chicago, USA)
• [Presentation] Constitutive SIRT1 overexpression impairs mitochondrial function inmice. (2010)
  • Author(s): Kawashima T, Inuzuka Y, Okuda J, Kato T, Niizuma S, Tamaki Y, Narazaki M, Matsuda T, Adachi S, Takemura G, Kita T, Kimura T, Shioi T.
  • Organizer: The 82th Scientific Sessions of American Heart Association
  • Place of Presentation: Chicago, USA
• [Presentation] A constitutive activation of phosphoinositide 3-kinase modifies cardiac aging in mice. (2010)
  • Author(s): Niizuma S, Inuzuka Y, Okuda J, Kawashima T, Kato T, Tamaki Y, Kawamoto A, Iwanaga Y, Yoshida Y, Kosugi R, Watanabe-maeda K, Machida Y, Tsuji S, Aburatani H, Izumi T, Kita T, Kimura T, Shioi T.
  • Organizer: The 82th Scientific Sessions of American Heart Association
  • Place of Presentation: Chicago, USA
• [Presentation] Overexpression of phosphoglycerate mutase, a glycolytic enzyme, induces proinflammatory response and impairs cardiac function. (2010)
  • Author(s): Okuda J, Niizuma S, Kato T, Inuzuka Y, Kawashima T, Tamaki Y, Iwanaga Y, Kita T, Kimura T, Shioi T.
  • Organizer: The 82th Scientific Sessions of American Heart Association
  • Place of Presentation: Chicago, USA
• [Presentation] Analysis of Metabolic Remodeling in the Transition From Cardiac Hypertrophy to Failure (2009)
  • Author(s): Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, Iwanaga Y, Narazaki M, Matsuda T, Soga T, Kimura T, Kita T, Shioi T.
  • Organizer: The 81th Scientific Sessions of American Heart Association
  • Place of Presentation: Orange County Convention Center(Orlando, USA)
  • Year and Date: 2009-11-18
• [Presentation] Analysis of Metabolic Remodeling in the Transition From Cardiac Hypertrophy to Failure. (2009)
  • Author(s): Kato T, Niizuma, S, Inuzuka Y, Kawashima, T, Okuda J, Tamki Y, Iwanaga Y, Narazaki M, Matsuda T, Soga T, Kimura T, Kita T, Shioi T.
  • Organizer: The 81th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, USA.
  • Year and Date: 2009-11-18
• [Book] エビデンスに基づく循環器病予防医学「老化と予防」 (2011)
  • Author(s): 塩井哲雄、新妻晋一郎
  • Publisher: 南山堂
• [Book] エビデンスに基づく循環器病予防医学、「老化と予防」 (2011)
  • Author(s): 塩井哲雄、新妻晋一郎
  • Publisher: 南山堂
• [Book] 疾患モデルの作成と利用、循環器疾患、遺伝子改変動物(心肥大・心不全) (2010)
  • Author(s): 塩井哲雄
  • Publisher: エル・アイ・シー
• [Remarks]
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/sinfuzen/http://kyoto-u-cardio.jp/kisokenkyu/sinfuzen/
• [Remarks]
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/sinfuzen/