Novel therapeutic approach for heart failure by promoting nuclear translocation of SIRT1, a protein deacetylase

• Project/Area Number: 23591085
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Sapporo Medical University
• Principal Investigator: TANNO Masaya 札幌医科大学, 医学部, 講師 (00398322)
• Co-Investigator(Kenkyū-buntansha): MIURA Tetsuji 札幌医科大学, 医学部, 教授 (90199951) ; HORIO Yoshiyuki 札幌医科大学, 医学部, 教授 (30181530)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 心不全 / SIRT1 / 酸化ストレス / 糖尿病 / 細胞死

Research Abstract

Nuclear translocation of SIRT1 suppresses cardiomyocyte death in failing hearts. We demonstrated that phosphorylation of Ser517 of SIRT1 by Akt/PI3K contributed to the nuclear translocation. Furthermore, we identified proteins whose binding to SIRT1 change during oxidative stress, using immunoprecipitation, 2D gel electrophoresis and mass spectrometry. The physiological significance of the protein-protein interaction is currently under investigation. To translate the cardioprotective function of activation or nuclear translocation of SIRT1, we first analyzed a characteristics of OLETF rats, obese insulin-resistant type 2 diabetes rats, as an in vivo animal model for heart failure. In this model, diastolic dysfunction was induced under pressure overload, but not physiological conditions, and the mechanisms that trigger the functional impairment was explored in detail. We are currently investigating whether and how SIRT1 modifies the development of diastolic dysfunction.

Research Products

• [Journal Article] Reversal of metabolic shift in post-infarct remodelled hearts: possible novel therapeutic approach. (2013)
  • Author(s): Tanno M, Kuno A.
  • Journal Title: Cardiovasc Res Volume: 97 Issue: 2 Pages: 195-196
  • DOI: 10.1093/cvr/cvs364
  • Peer Reviewed
• [Journal Article] Resveratrol improves cardiomyopathy in dystrophin-deficient mice through SIRT1 Protein-mediated modulation of p300 Protein. (2013)
  • Author(s): Kuno A et al.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 8 Pages: 5963-5972
  • DOI: 10.1074/jbc.m112.392050
  • Peer Reviewed
• [Journal Article] The mPTP and its regulatory proteins : final common targets of signalling pathways for protection against necrosis (2012)
  • Author(s): Miura T, Tanno M
  • Journal Title: Cardiovasc Res Volume: 94 Issue: 2 Pages: 181-9
  • DOI: 10.1093/cvr/cvr302
  • Peer Reviewed
• [Journal Article] Emerging beneficial roles of sirtuins in heart failure. (2012)
  • Author(s): Tanno M et al.
  • Journal Title: Basic Res Cardiol. Volume: 107 Issue: 4 Pages: 273-273
  • DOI: 10.1007/s00395-012-0273-5
  • Peer Reviewed
• [Journal Article] Role of connexin-43 in protective PI3K-Akt-GSK-3βsignaling in cardiomyocytes (2012)
  • Author(s): Ishikawa S, Kuno A, Tanno M, Miki T, Kouzu H, Itoh T, Sato T, Sunaga D, Murase H, Miura T
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 302 Issue: 12 Pages: H2536-H2544
  • DOI: 10.1152/ajpheart.00940.2011
  • Peer Reviewed
• [Journal Article] Role of ER Stress in Ventricular Contractile Dysfunction in Type 2 Diabetes (2012)
  • Author(s): Takada A, Miki T, Kuno A, Kouzu H, Sunaga D, Itoh T, Tanno M, Yano T, Sato T, Ishikawa S, Miura T
  • Journal Title: PLoS One Volume: 7 Issue: 6 Pages: e39893-e39893
  • DOI: 10.1371/journal.pone.0039893
  • Peer Reviewed
• [Journal Article] Cytoprotective regulation of the mitochondrial permeability transition pore is impaired in type 2 diabetic Goto-Kakizaki rat hearts (2012)
  • Author(s): Itoh T, Kouzu H, Miki T, Tanno M, Kuno A, Sato T, Sunaga D, Murase H, Miura T
  • Journal Title: J Mol Cell Cardiol Volume: 53 Issue: 6 Pages: 870-9
  • DOI: 10.1016/j.yjmcc.2012.10.001
  • Peer Reviewed
• [Journal Article] Histopathology of the pancreas in fulminant type 1 diabetes after 23-year follow-up : a case report (2012)
  • Author(s): Sato T, Miki T, Murakami N, Hirohashi Y, Kouzu H, Furuhashi M, Tanno M, Yuda T, Saitoh S, Hasegawa T, Miura T
  • Journal Title: Pathology International Volume: 62 Issue: 12 Pages: 827-29
  • DOI: 10.1111/pin.12017
  • Peer Reviewed
• [Journal Article] 高齢者の心不全の病態、臨床的特徴と診断・治療上の注意点 (2012)
  • Author(s): 丹野雅也、三浦哲嗣
  • Journal Title: 月刊循環器 Circulation Volume: 2 Pages: 38-50
• [Journal Article] Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection (2011)
  • Author(s): Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, Sato T, Kouzu H, Shimamoto K and Miura T
  • Journal Title: Hypertension Volume: 57 Issue: 1 Pages: 110-5
  • DOI: 10.1161/hypertensionaha.110.158469
  • Peer Reviewed
• [Journal Article] Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy (2011)
  • Author(s): Hori SY, et al
  • Journal Title: J.Pharmacol.Exp.Ther. Volume: 338 Issue: 3 Pages: 784-794
  • DOI: 10.1124/jpet.111.183210
  • Peer Reviewed
• [Presentation] Insufficient ATP supply due to excessive degradation of adenine nucleotides underlies afterload-induced diastolic dysfunction in type 2 diabetic heart (2013)
  • Author(s): Kouzu H, Miki T, Tanno M, Kuno A, Yano T, Murase H, Tobisawa T, Ogasawara M, Miura T
  • Organizer: 第17回日本心不全学会
  • Place of Presentation: 大宮
  • Year and Date: 2013-11-30
• [Presentation] The Role of mTORC2 and Ribosomal Protein S6 in Cardioprotective Signaling (2013)
  • Author(s): Yano T, Felito M, Tobisawa T, Ogasawara M, Murase H, Kuno A, Tanno M, Miki T, Steenbergen C, Miura T
  • Organizer: 第17回日本心不全学会
  • Place of Presentation: 大宮
  • Year and Date: 2013-11-28
• [Presentation] Activation of the glucagon-like peptide-1 receptor restores myocardial autophagic flux and reduces mortality after myocardial infarction in diabetic rats (2013)
  • Author(s): Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Tobisawa T, Ogasawara M, Ishikawa S, Miura T
  • Organizer: American Heart Association 2013
  • Place of Presentation: Dallas, TX, U.S.A.
  • Year and Date: 2013-11-17
• [Presentation] Activation of the mitochondrial ATP-sensitive potassium channel achieves cell protection by promoting re-closure of the mPTP via suppression of GSK-3β-complex III interaction (2013)
  • Author(s): Tanno M, Sunaga D, Miki T, Kuno A, Kouzu H, Sato T, Ishikawa S, Ogasawara M, Tobisawa T, Miura T
  • Organizer: European Society of Cardiology Congress 2013
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 2013-09-03
• [Presentation] Type 2 diabetes induces ventricular electrical remodeling with a transmural gradient (2013)
  • Author(s): Tobisawa T, Sato T, Yuda S, Miki T, Tanno M, Kuno A, Kobayashi T, Akasaka H, Tohse N, Miura T
  • Organizer: European Society of Cardiology Congress 2013
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 2013-09-02
• [Presentation] Mechanisms underlying mitochondrial translocation of GSK-3β, a crucial inducer of mitochondrial permeability transition : GSK-3βactivity, interaction with VDAC2 and a mitochondrial targeting sequence (2013)
  • Author(s): Tanno M, Kuno A, Ishikawa S, Ogasawara M, Tobisawa T, Murase H, Sato T, Kouzu H, Miki T, Miura T
  • Organizer: Basic Cardiovascular Sciences 2013 (AHA)
  • Place of Presentation: Las Vegas, NV, U.S.A.
  • Year and Date: 2013-07-23
• [Presentation] Type 2 diabetes induces subendocardium-predominant reduction of transient outward K+ current via downregulation of Kv4.2 and KChIP2 (2013)
  • Author(s): Sato T, Kobayashi T, Kuno K, Murase H, Kouzu H, Tanno T, Miki T, Miura T, Tohse N
  • Organizer: The 50th International Society of Heart Research Japanese Section
  • Place of Presentation: San Diego, CA, U.S.A.
  • Year and Date: 2013-06-29
• [Presentation] Mechanisms of mPTP re-closure by activation of the mitochondrial ATP-sensitive K+ channel : suppression of GSK-3β-Rieske interaction and ROS production after oxidative stress (2013)
  • Author(s): Sunaga D, Tanno T, Ishikawa S, Kuno A, Sato T, Kouzu H, Miki T, Miura T
  • Organizer: The 50th International Society of Heart Research Japanese Section
  • Place of Presentation: San Diego, CA, U.S.A.
  • Year and Date: 2013-06-29
• [Presentation] Role of SIRT3, a Mitochondrial Protein Deacetylase, in Type 2 Diabetic Myocardium (2013)
  • Author(s): Kuno A, Itoh T, Sato T, Kouzu H, Tanno M, Miki T, Horio Y, Miura T
  • Organizer: 第77回日本循環器学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-17
• [Presentation] Promotion of Re-closure of the mPTP Underlies Cardiomyocyte Protection by Activation of the Mitochondrial KATP Channel against ROS-induced Necrosis (2013)
  • Author(s): Sunaga D, Kuno A, Ishikawa S, Miki T, Tanno M, Kouzu H, Itoh T, Sato T, Murase H, Miura T
  • Organizer: 第77回日本循環器学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-17
• [Presentation] Interaction with VDAC2 Promotes Mitochondrial Translocation of GSK3Βin a Kinase Activity-Dependent Manner and Induces Cell Death (2013)
  • Author(s): Tanno M, Ishikawa S, Miki T, Kuno A, Kouzu H, Itoh T, Sato T, Sunaga D, Murase H, Miura T
  • Organizer: 第77回日本循環器学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-16
• [Presentation] Changes in Titin-based Ventricular Stiffness May Underlie Diastolic Dysfunction Unmasked by Acute Systolic Pressure Overloading in Type 2 Diabetic Hearts (2013)
  • Author(s): Kouzu H, Kuno A, Miki T, Tanno M, Itoh T, Sato T, Sunaga D, Murase H, Miura T
  • Organizer: 第77回日本循環器学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-16
• [Presentation] Interaction of Cyclophilin D with Inorganic Phosphate Carrier during Ischemia Determines Threshold for mPTP Opening and Reperfusion-induced Cell Necrosis (2013)
  • Author(s): Ito T, Miki T, Tanno M, Kuno A, Kouzu H, Sato T, Sunaga D, Murase H, Ishikawa S, Miura T
  • Organizer: 第77回日本循環器学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-16
• [Presentation] Iroquois Homeodomain 5 (Irx5) is Upregulated via Increased ER Stress in Type 2 Diabetic Hearts (2013)
  • Author(s): Sato T, Kuno A, Kobayashi T, Miki T, Tanno M, Ishikawa S, Miura T, Tohse N
  • Organizer: 第77回日本循環器学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-15
• [Presentation] Type 2 diabetes induces ventricular electrical remode ling with a transmural gradient (2013)
  • Author(s): Tobisawa T, Sato T, Yuda S, Miki T, Tanno M, Kuno A, Kobayashi T, Akasaka H, Tohse N, Miura T.
  • Organizer: European Society of Cardiology
  • Place of Presentation: Amsterdam
• [Presentation] Insufficient ATP supply due to excessive degradation of adenine nucleotides underlies afterload - induced diastolic dysfu nction in type 2 diabetic heart (2013)
  • Author(s): Kouzu H, Miki T, Tanno M, Kuno A, Yano T, Murase H, To bisawa T, Ogasawara M, Miura T
  • Organizer: 日本心不全学会
  • Place of Presentation: 大宮
• [Presentation] a SIRT1 activator, prevents cardiomyopathy in dystrophin-deficient mice by down- regulation of p300 (2012)
  • Author(s): Kuno A, Tanno M, Miki T, Ishikawa S, Horio Y, Miura T
  • Organizer: European Society of Cardiology Congress 2012
  • Place of Presentation: Munich, Germany
  • Year and Date: 2012-08-26
• [Presentation] Resveratrol, a SIRT1 activator, prevents cardiomyopathy in dystrophin-deficient mice by down-regulation of p300 (2012)
  • Author(s): Kuno A, Tanno M, Miki T, Ishikawa S, Horio Y, Miura T.
  • Organizer: European Society of Cardiology Congress 2012
  • Place of Presentation: Munich
• [Presentation] Phosphorylation of GSK-3b at Ser9 inhibits its translocation to mitochondria and attenuates lethal ROS production by mitochondria (2012)
  • Author(s): Masaya Tanno, Takayuki Miki, Atsushi Kuno, Hidemichi Kouzu, Takahito Itoh, Tatsuya Sato, Daisuke Sunaga and Tetsuji Miura
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡
• [Presentation] GSK-3b translocates to mitochondria by oxidant stress in a kinase activity-dependent manner and contributes to lethal ROS production (2011)
  • Author(s): Masaya Tanno, Takayuki Miki, Atsushi Kuno, Hidemichi Kouzu, Takahito Itoh, Tatsuya Sato, Daisuke Sunaga and Tetsuji Miura
  • Organizer: Scientific Sessions 2011, American Heart Association
  • Place of Presentation: Orlando, USA
• [Presentation] 心不全発症進展における長寿蛋白SIRT1の機能とその分子機序
  • Author(s): 丹野雅也
  • Organizer: 日本適応医学会第15回学術集会(招待講演)
  • Place of Presentation: 浜松