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Normalization of increased protein phosphatase 1 activity by using an high efficiency myocardial gene transfer technique in chronic heart failure

Research Project

Project/Area Number 15590754
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionYamaguchi University

Principal Investigator

IKEDA Yasuhiro  Yamaguchi University, School of Medicine, Research Associate, 医学部, 寄附講座教員 (00260349)

Co-Investigator(Kenkyū-buntansha) YANO Masafumi  Yamaguchi University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (90294628)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
Keywordschronic heart failure / dilated cardiomyopathy / protein phosphatase 1 / adenovirus vector / adeno-associated virus vector / cardiomyopathic hamster / high-efficiency in vivo myocardial gene transfer / アデノウイルスベクター / アデノ関連ウイルスベクター / 高効率心筋遺伝子導入
Research Abstract

Background : The type 1 protein phosphatase (PP1) has been reported to be overactivated in experimental and human failing hearts, leading to a depression of Ca^<2+> cycling and contractility. We previously reported that increased PP1 activity was also observed in the models of genetic cardiomyopathy, UMX cardiomyopathic(CM) hamster, and in vivo inhibition of PPl by overexpressing inhibitor-2(I-2) improved short-term cardiac function. Method and Results : We here investigated the effect of chronic PP1 inhibition by using high efficiency adeno-associated virus (rAAV-) mediated cardiac I-2 gene delivery on heart failure progression and survival in CM hamster. Endogeonus inhibitor-2 (I-2) was only detected in the microsomal fraction of cardiomyocytes, and adenoviral overexpresion of I-2 preferentially localized in the sarcolemma, suggesting that I-2 is a membrane-bound (m-) endogenous PP1 inhibitor. In addition, PP1 activity following adenovirus I-2 transfection in cardiomyocytes dramatically decreased PP1 activity and augmented Ca^<2+> cycling and cell shortening in cardiomyocytes. rAAV-mediated in vivo cardiac I-2 gene delivery restored cardiac function and extended survival time for 3 months in CM hamsters. Conclusions: These findings suggest that increased m- PP1 in cardiomyocytes is an important contributor of depressed Ca2+ cycling, and inhibition of m- PP1 via inhibitor-2 may provide a new molecular target for the treatment of heart failure.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (14 results)

All 2005 2004 Other

All Journal Article (12 results) Book (1 results) Publications (1 results)

  • [Journal Article] Altered intracellular Ca2+ handling in heart failure2005

    • Author(s)
      Yano Masafumi, Yasuhiro Ikeda, Masunori Matsuzaki
    • Journal Title

      J Clin Invest. 115

      Pages: 556-564

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Defective regulation of inter-domain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure2005

    • Author(s)
      Oda T et al.
    • Journal Title

      Circulation (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sorcin interacts with sarcoplasmic reticulum Ca2+-ATPase and modulates excitation-contraction coupling in the heart2005

    • Author(s)
      Matsumoto T et al.
    • Journal Title

      Bas Res Cardiol 100

      Pages: 250-62

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Altered intracellular Ca2+ handling in heart failure2005

    • Author(s)
      Yano M, Ikeda Y, Matsuzaki M
    • Journal Title

      J Clin Invest 115

      Pages: 556-564

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Defective regulation of inter-domain interaction within the ryanodine receptor plays a key role in the pathogenesis of heart failure2005

    • Author(s)
      Oda T, Yano M, Yamamoto T, Tokuhisa T, Okuda, S, Doi M, Ohkusa T, Ikeda Y, Kobayashi, S, Ikemoto N, Matsuzaki M
    • Journal Title

      Circulation (in print)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sorcin interacts with sarcoplasmic reticulum Ca2+ ATPase and modulates excitation-contraction coupling in the heart.2005

    • Author(s)
      Matsumoto T, Hisamatsu Y, Ohkusa T, Inoue N, Sato T, Suzuki S, Ikeda Y, Matsuzaki M
    • Journal Title

      Bas Res Cardiol 100

      Pages: 250-262

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Myocardial gene therapy as a prototype prodrug delivery System for intractable heart failure2005

    • Author(s)
      Ikeda Y, Yamada M, Matsuzaki M
    • Journal Title

      Molecular Mechanism in Heart Disease (edited by Mizukami, Ohkusa)(Research Signpost) (in print)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Defective regulation of inter-domain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure2005

    • Author(s)
      Oda T et al.
    • Journal Title

      Circulation (in print)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Sorcin interacts with sarcoplasmic reticulum Ca2+-ATPase and modulates excitation-contraction coupling in the heart2005

    • Author(s)
      Matsumoto T et al.
    • Journal Title

      Bas Res Cardiol (in print)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 心不全の遺伝子治療としてのCa2+制御蛋白2005

    • Author(s)
      池田 安宏
    • Journal Title

      Heart View 9

      Pages: 149-154

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 心不全に対する心筋遺伝子治療の開発2005

    • Author(s)
      池田 安宏
    • Journal Title

      心臓 37

      Pages: 100-107

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 心不全に対する遺伝子治療の開発と展望2004

    • Author(s)
      池田 安宏, 山田 倫生, 松崎 益徳
    • Journal Title

      ケミカルエンジニアリング 49

      Pages: 19-24

    • Related Report
      2004 Annual Research Report
  • [Book] myocardial gene therapy as a prototype prodrug delivery system for intractable heart failure (Molecular Mechanism of Heart Diseases (edited by Dr.Mizukami))2005

    • Author(s)
      Ikeda Y, Yamada M, Matsuzaki M
    • Publisher
      Research Signpost(in press)
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Yoshitaka Iwanaga: "Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats"J Clin Invest. 113. 727-736 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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