Clarification of mechanisms to regulate the activity of protein deacetylase SIRT1 and its therapeutic application in heart failure

• Project/Area Number: 20590869
• 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: Sapporo Medical University
• Principal Investigator: TANNO Masaya Sapporo Medical University, 医学部, 助教 (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): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); 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 / エピジェネティクス / ヒストン脱アセチル化酵素 / 細胞内局在 / 酸化ストレス / 細胞死

Research Abstract

SIRT1 shuttled between the nuclei and cytoplasm. Nuclear SIRT1 suppressed oxidative stress-induced cell death by up-regulating Mn-SOD. SIRT1 accumulated in nuclei in cardiomyocytes of failing hearts probably as an endogenous adaptive mechanism and activation of SIRT1 by resveratrol reduced the mortality in cardiomyopathic hamsters. These findings suggest that SIRT1 activator may be a novel therapeutic approach for chronic heart failure.

Research Products

• [Journal Article] Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection. (2010)
  • Author(s): Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, Sato T, Kouzu H, Shimamoto K Miura T.
  • Journal Title: Hypertension 57 Pages: 110-115
  • Peer Reviewed
• [Journal Article] Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure (2010)
  • Author(s): Tanno M, Kuno A, Yano T, Miura T, Hisahara S, Ishikawa S, Shimamoto K, Horio Y.
  • Journal Title: J Biol Chem 285 Pages: 8375-82
  • Peer Reviewed
• [Journal Article] Protein deacetylase SIRT1 in the cytoplasm promotes nerve growth factor-induced neurite outgrowth in PC12 cells (2010)
  • Author(s): Sugino T, Maruyama M, Tanno M, Kuno A, Houkin K, Horio Y.
  • Journal Title: FEBS Lett 584 Pages: 2821-6
  • Peer Reviewed
• [Journal Article] Mitochondrial kinase signalling pathways in myocardial protection fromischaemia/reperfusion-induced necrosis (2010)
  • Author(s): Miura T, Tanno M, Sato T.
  • Journal Title: Cardiovasc Res 88 Pages: 7-15
  • Peer Reviewed
• [Journal Article] Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure (2010)
  • Author(s): Tanno M, et al.
  • Journal Title: J Biol Chem 285 Pages: 8375-8382
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phospho-glycogen synthase kinase 3beta-mediated suppression of mitochondrial permeability transition (2009)
  • Author(s): Miki T, Miura T, Hotta H, Tanno M, Yano T, Sato T, Ishikawa S, Shimamoto K.
  • Journal Title: Diabetes 58 Pages: 2863-72
  • Peer Reviewed
• [Journal Article] Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation (2008)
  • Author(s): Hisahara S, Chiba S, Matsumoto H, Tanno M, Yagi H, Shimohama S, Horio Y.
  • Journal Title: Proc Natl Acad Sci U S A 105 Pages: 15599-15604
  • Peer Reviewed
• [Presentation] Activation of Sirt1 suppresses hypertrophic response of cardiomyocytes by inhibition of H3K9 acetylation via p roteasome-mediated p300 degradation. (2010)
  • Author(s): Kuno A, Tanno M, Ishikawa S, Horio Y, Miura T.
  • Organizer: 83^<rd> Scientific Session of American Heart Association
  • Place of Presentation: Chicago,U.S.A.
• [Presentation] Activation of Sirtl suppresses hypertrophic response of cardiomyocytes by inhibition of H3K9 acetylation via proteasome-mediated p300 degradation. (2010)
  • Author(s): Masaya Tanno
  • Organizer: 2010年度アメリカ心臓協会学術集会
  • Place of Presentation: アメリカ合衆国シカゴ
• [Presentation] The SIRT1 activator resveratrol suppresses cardiomy ocyte hypertrophy by promoting histone H3 Lys9 deacetylation and tri-methylation. (2009)
  • Author(s): Kuno A, Tanno M, Yano T, Takada A, Miura T, Horio Y, Shimamoto K.
  • Organizer: 82^<nd> Scientific Session of American Heart Association
  • Place of Presentation: Orlando, U.S.A.
• [Presentation] Activation of histone/protein deacetylase SIRT1 by resveratrol induces MnSOD up-regulation via FOXO3a and improves survival of heart failure animals. (2009)
  • Author(s): Kuno A, Tanno M, Miura T, Horio Y, Shimamoto K.
  • Organizer: 31^<st> Congress of the European Society of Cardiology
  • Place of Presentation: Barcelona,Spain
• [Presentation] The SIRT1 activator resveratrol suppresses cardiomyocyte hypertrophy by promoting histone H3 Lys9 deacetylation and tri-methylation (2009)
  • Author(s): Kuno A, Tanno M, et al.
  • Organizer: アメリカ心臓病学会
  • Place of Presentation: Orlando, USA
• [Presentation] Activation of histone/protein deacetylase SIRT1 by resveratrol induces MnSOD up-regulation via FOXO3a and improves survival of heart failure animals (2009)
  • Author(s): Kuno A, Tanno M, et al.
  • Organizer: ヨーロッパ心臓病学会
  • Place of Presentation: Barcelona, Spain
• [Presentation] Resveratrol, a SIRT1 activator, modifies epigenetic histone acetylation/methylation status and suppresses cardiomyocyte hypertrophy (2009)
  • Author(s): Kuno A, Tanno M, et al.
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] Activation of a protein deacetylase, SIRTl, by resveratrol suppresses progression of heart failure and improves survival by up-regulation of MnSOD (2008)
  • Author(s): Masaya Tanno
  • Organizer: Scientific Sessions 2008 of the American Heart Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2008-11-10
• [Presentation] Activation of a protein deacetylase,SIRT1, by resveratrol suppresses progression of heart failure and improves survival by up-regulation of Mn-SOD. (2008)
  • Author(s): Tanno M, Kuno A, Miki T, Miura T, Horio Y, Shimamoto K.
  • Organizer: 81^<st> Scientific Session of American Heart Association
  • Place of Presentation: New Orleans, U.S.A.
• [Presentation] Resveratrol, an activator of protein deacetylase SIRT1, suppresses oxidative stress-induced cell death by upregulating MnSOD expression through transactivation of FOXO3a . (2008)
  • Author(s): Kuno A, Tanno M, Miura T, Horio Y, Shimamoto K.
  • Organizer: 81^<st> Scientific Session of America n Heart Association
  • Place of Presentation: New Orleans,U.S.A.