新規の心筋解糖系シグナロソームの発見とインスリン抵抗性心不全病態のエネルギー代謝

• Project/Area Number: 23229006
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: 松原 弘明 京都府立医科大学, 医学(系)研究科(研究院), 教授 (10239072)
• Co-Investigator(Kenkyū-buntansha): 的場 聖明 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10305576) ; 上山 知己 京都府立医科大学, 医学(系)研究科(研究院), 講師 (80379388) ; 池田 宏二 京都府立医科大学, 医学(系)研究科(研究院), 助教 (90423871)
• Project Period (FY): 2011-05-31 – 2014-03-31
• Project Status: Declined (Fiscal Year 2013)
• Budget Amount: ¥151,580,000 (Direct Cost: ¥116,600,000、Indirect Cost: ¥34,980,000); Fiscal Year 2013: ¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000); Fiscal Year 2012: ¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000); Fiscal Year 2011: ¥66,300,000 (Direct Cost: ¥51,000,000、Indirect Cost: ¥15,300,000)
• Keywords: 心不全 / インスリン抵抗性 / エネルギー代謝

Research Abstract

①心筋において、p53の下流標的蛋白であるTIGARは、解糖系の代謝を抑制しているが、TIGAR-KOマウスでは、ミトコンドリアの質を維持し、梗塞後のリモデリング抑制を来すことを発見した。エネルギー代謝およびミトファジーを介し心筋細胞の恒常性制御を行っていることを証明した。また圧負荷心不全モデルにおいては、TIGARは解糖系抑制により心不全悪化を来すことを証明発表した。
②心筋細胞のカベオラに集積しているβ１受容体とMURCの役割について検討した。MURCは、β１受容体と心筋細胞膜に共局在しており、培養心筋細胞においてMURCをknockdownするとβ１受容体刺激によるcAMP産生抑制と心筋細胞肥大が抑制され、MURC-KOマウスではβ１受容体刺激による心肥大と圧負荷による心不全発症が抑制されることを見出した。これらの結果より、MURCがβ１受容体を介した心不全発症に重要な役割を果たしていることが明らかにできた。
③心筋細胞死におけるARIAの機能解析を行うためにラット横紋筋細胞のH9C2を用いてARIAを発現する細胞株を作成した。DOX刺激による細胞死はARIA過剰発現により増加した。そのメカニズムとしてARIAはPTENの細胞膜局在を増加し、細胞生存シグナルであるPI3K/Aktを減弱させることを証明した。さらにARIA-KOマウスにDOXを投与してストレス誘導性心不全におけるARIAの機能を解析した。野生型マウスではDOX投与により心筋細胞死・左室壁の菲薄化・心筋線維化が発生し、心収縮能は低下した。一方、ARIA-KOでは心収縮能は有意に維持されており、心筋細胞死・左室壁の菲薄化・心筋線維化はいずれも軽減していた。これら結果からARIAはPTEN/PI3Kパスウェイの調節を介して心筋細胞死を制御し、ストレス誘導生心不全の発症に関与していることが明らかにできた。

Current Status of Research Progress

Reason

翌年度、交付申請を辞退するため、記入しない。

Strategy for Future Research Activity

翌年度、交付申請を辞退するため、記入しない。

Research Products

• [Journal Article] TIGAR axis attenuates mitophagy to exacerbate cardiac damage after ischemia (2012)
  • Author(s): Hoshino A, Matoba S, et. al
  • Journal Title: J Mol Cell Cardiol Volume: 52 Issue: 1 Pages: 175-84
  • DOI: 10.1016/j.yjmcc.2011.10.008
  • Peer Reviewed
• [Journal Article] promotes cardiac dysfunction in diabetic mellitus due to excessive mitochondrial respiration-mediated ROS generation and lipid accumulation Circ- Heart Fail (2012)
  • Author(s): Nakamura H, Matoba S, Iwai-Kanai E, Kimata M, Hoshino A, Nakaoka M, Katamura M, Okawa Y, Mita Y, Ikeda K, Okigaki M, Adachi S, Tanaka H, Takamatsu T, Matsubara H
  • Journal Title: Eur Heart J. Volume: 5巻 Issue: 1 Pages: 106-115
  • DOI: 10.1161/circheartfailure.111.961565
  • Peer Reviewed
• [Journal Article] Apoptosis regulator through modulating IAP expression (ARIA) controls the PI3K/Akt pathway in endothelial and endothelial progenitor cells (2011)
  • Author(s): Koide M, et al
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108 Issue: 23 Pages: 9472-9477
  • DOI: 10.1073/pnas.1101296108
  • Peer Reviewed
• [Journal Article] Molecular Genetic and Functional Characterization Implicate Muscle-Restricted Coiled-Coil Gene (MURC) as a Causal Gene for Familial Dilated Cardiomyopathy (2011)
  • Author(s): Rodriguez G, et al
  • Journal Title: Circ Cardiovasc Genet Volume: 4 Issue: 4 Pages: 349-358
  • DOI: 10.1161/circgenetics.111.959866
  • Peer Reviewed
• [Presentation] p53-mediated regulation of mitophagy rescued heart failure in mouse model (2013)
  • Author(s): Matoba S, et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] G-CSF prevent of doxorubicin induced cardio toxicity by suppression of p53 upregulation. (2013)
  • Author(s): Mita Y, et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] Stabilizing mitochondria by autophagy protects cardiac myocytes during α1-adrenergic stimulation. (2013)
  • Author(s): Katamura M, et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] TIGAR (TP53-induced glycolysis and apoptosis regulator) reduces glycogenic energy metabolism and deteriorates left ventricular function in pressure overload-induced heart failure model. (2013)
  • Author(s): Okawa Y, et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC/Cavin-4 Negatively Regulates Protective Effects of Caveolin-3 in Cardiac Function. (2013)
  • Author(s): Naito D, et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC/Cavin-4, a Muscle-restricted Caveolar Scaffolding Protein for Activated ERK, Regulates Cardiac Hypertrophy Induced by α1-Adrenergic Agonist. (2013)
  • Author(s): Ogata T, et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] ARIA modifies the plaque vulnerability through the control of macrophage foam cell formation (2013)
  • Author(s): Matsuo, D. et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] ARIA regulates the cardiomyocyte death in doxorubicin-induced cardiomyopathy by modulating the PI3K/Akt/Bad pathway (2013)
  • Author(s): Kitamura Y, et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] Inhibition of Cytosolic p53 Preserves Mitochondrial Integrity and Prevents Cardiac Aging. (2012)
  • Author(s): Hoshino A, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] Curcumin Prevents Doxorubicin-Induced Cardiotoxicity Through Phosphorylated Bcl-2-Regulated Autophagy. (2012)
  • Author(s): Katamura, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] p53 activation provokes mitochondrial compromise and cardiac aging. (2012)
  • Author(s): Hoshino A, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] MURC/cavin-4 Functions as a Negative Regulator of Caveolin-3 in The Development of Heart Failure. (2012)
  • Author(s): Naito D, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] MURC/Cavin-4, a New Caveolar Scaffolding Protein for Activated ERK, Regulates Cardiac Hypertrophy Induced by α1-Adrenergic Agonist. (2012)
  • Author(s): Ogata T, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] ARIA regulates the Cardiomyocyte Death in Doxorubicin-induced Cardiomyopathy by Modulating the PI3k/ Akt/ Bad Pathway (2012)
  • Author(s): Kitamura Y, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] ARIA (Apoptosis Regulator Through Modulating Iap Expression) Regulates Insulin Sensitivity and Predisposition to Obesity Through a Modification of Endothelial Cell Functions (2012)
  • Author(s): Akakabe Y, et al
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] The Anti-atherosclerotic Effect of Statin is Augmented In Patients With Impaired Renal Function: A Sub-analysis of The PEACE Study (2012)
  • Author(s): Shimoda Y, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] ARIA Modifies the Plaque Vulnerability Through the Control of Endoplasmic Reticulum Stress-Induced Macrophage Apoptosis (2012)
  • Author(s): Matsuo K, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] Granulocyte Colony-Stimulating Factor (G-CSF) Reduced Doxorubicin Induced Cardiotoxicity by Stabilizing MDM2-p53 Interaction (2012)
  • Author(s): Mita Y, et al.
  • Organizer: 第29回 国際心臓研究学会(ISHR)日本部会総会
  • Place of Presentation: 福岡
• [Presentation] Impairment of MURC/cavin-4 localization to caveolae causes progressive cardiac dysfunction and intraventricular conduction delay. (2012)
  • Author(s): Naito D, et al.
  • Organizer: 第29回 国際心臓研究学会(ISHR)日本部会総会
  • Place of Presentation: 福岡
• [Presentation] MURC/Cavin-4 is a New Caveolar Scaffolding Protein for Phosphorylated ERK and Regulates α1-adrenergic Agonist-induced Cardiomyocyte Hypertrophy. (2012)
  • Author(s): Ogata T, et al.
  • Organizer: 第49回日本臨床分子医学会学術集会
  • Place of Presentation: 京都
• [Presentation] p53 Promotes Cardiac Dysfunction in Diabetes Mellitus by Excessive Mitochondrial Respiration and Fat/CD36 Upregulation (2012)
  • Author(s): Matoba S, et al
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
• [Presentation] Granulocyte Colony-stimulating Factor (G-CSF) Protects Cardiac Myocytes Against Doxorubicin Induced Injury Via the Stabilization of MDM2 (2012)
  • Author(s): Mita Y, et al
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
• [Presentation] Stabilizing mitochondria by autophagy protects cardiac myocytes during α1-adrenergic stimulation (2012)
  • Author(s): Nakaoka M, et al
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
• [Presentation] Curcumin Protect Mice Heart against Doxorubicin Induced Cardiomyopathy thorough the Induction of Autophagy (2012)
  • Author(s): Katamura M, et al
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
• [Presentation] Caveolae-related genes in heart failure and arrhythmia (2012)
  • Author(s): Ueyama T, et al
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
• [Presentation] MURC functions as a caveolar scaffold protein for Rho signaling that regulates proliferation and migration of vascular smooth muscle cells (2012)
  • Author(s): Nakanishi N, et al
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
• [Presentation] Loss of MURC Targeting to Caveolae Causes Progressive Cardiac Dysfunction and Intraventricular Conduction Delay (2012)
  • Author(s): Naito D, et al
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
• [Presentation] Genetic Deletion of ARIA Attenuates the Doxorabicin-induced Cardiomyopathy by Modulating the PI3K/Akt/Bad Pathway in Cardiomyocytes (2012)
  • Author(s): Kitamura Y, et al
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
• [Presentation] Vascular smooth muscle cells in the pathogenesis of vascular calcification : their distinctive roles in the plaque calcification and medial calcification (2012)
  • Author(s): Ikeda K, et al
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
• [Presentation] p53 promotes cardiac dysfunction in diabetes mellitus by excessive mitochondrial respiration and Fat/CD36 upregulation (2011)
  • Author(s): Nakamura H, et al
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Florida, USA
• [Presentation] p53-Tigar Axis Attenuates Mitophagy Tt Exacerbate Cardiac Damage After Ischemia (2011)
  • Author(s): Hoshino A, et al
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Florida, USA
• [Presentation] p53 promotes cardiac aging through the inhibition of parkin mediated mitochondrial quality control (2011)
  • Author(s): Hoshino A, et al
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Florida, USA
• [Presentation] p53 activation provokes mitochondrial compromise and cardiac aging (2011)
  • Author(s): Hoshino A, et al
  • Organizer: NHLB1 Mitochondrial biology symposium 2011
  • Place of Presentation: Maryland, USA
• [Presentation] p53 mediated inactivation of Bnip3 reduces mitophagy to aggravate cardiac damage after ischemic injury (2011)
  • Author(s): Hoshino A, et al
  • Organizer: 第75回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] G-CSFによる心筋保護効果と抗癌作用への影響 (2011)
  • Author(s): 三田雄一郎、的場聖明、星野温、中岡幹彦、片村真紀、大川善文、有吉真、足立壮一、松原弘明、金井恵理
  • Organizer: 第20回cell death学会
  • Place of Presentation: 東京
• [Presentation] クルクミンはドキソルビシンによる心筋障害に対し保護的に働く (2011)
  • Author(s): 片村真紀、的場聖明、星野温、中岡幹彦、大川善文、有吉真、三田雄一郎、足立壮一、松原弘明、金井恵理
  • Organizer: 第20回cell death学会
  • Place of Presentation: 東京
• [Presentation] p53発現抑制によるオートファジー亢進を介した心筋保護効果 (2011)
  • Author(s): 的場聖明、星野温、金井恵理、中村英夫、中岡幹彦、片村真紀、大川善文、有吉真、三田雄一郎、松原弘明
  • Organizer: 第34回日本高血圧学会総会
  • Place of Presentation: 宇都宮
• [Presentation] MURC regulates proliferation of vascular smooth muscle cells through the Rho/ROCK pathway (2011)
  • Author(s): Nakanishi N, et al
  • Organizer: 第75回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC, muscle-restricted coiled-coil protein, is a component of the caveolin-cavin complex and regulates caveolae morphology in cardiomyocytes (2011)
  • Author(s): Naito D, et al
  • Organizer: 第75回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC/Cavin-4のRho/ROCK pathwayを介した血管平滑筋機能制御メカニズムの検討 (2011)
  • Author(s): 中西直彦, 小形岳寛, 宮川浩太郎, 内藤大督, 谷口琢也, 天野克也, 上山知己, 松原弘明
  • Organizer: 第34回日本高血圧学会総会
  • Place of Presentation: 宇都宮
• [Presentation] Association of IL-6 but not hsCRP with subclinical carotid atherosclerosis : a sub-analysis of the PEACE study (2011)
  • Author(s): Ikeda K, et al
  • Organizer: European Society of Cardiology 2011
  • Place of Presentation: Paris, France
• [Presentation] Pitavastatin evaluation of atherosclerosis regression by intensive cholesterol-lowering therapy trial (PEACE study) (2011)
  • Author(s): Ikeda K, et al
  • Organizer: European Society of Cardiology 2011
  • Place of Presentation: Paris, France
• [Presentation] ARIA controls developmental and postnatal angiogenesis by regulating the PI3K/Akt/eNOS pathway (2011)
  • Author(s): Koide M, et al
  • Organizer: European Society of Cardiology 2011
  • Place of Presentation: Paris, France
• [Presentation] Identification of ARIA as novel factor in the pathophysiology of metabolic syndrome (2011)
  • Author(s): Akakabe Y, et al
  • Organizer: European Society of Cardiology 2011
  • Place of Presentation: Paris, France
• [Remarks] 京都府立大学循環器内科・腎臓内科
  • URL: http://www.f.kpu-m.ac.jp/k/med2/index.html
• [Remarks]
  • URL: http://www.f.kpu-m.ac.jp/k/med2/index.html