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Elucidating the mechanism of heart failure using mouse model of dilated cardiomyopathy

Research Project

Project/Area Number 13670719
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

KUBOTA Toru  Graduate School of Medical Sciences, Assistant Professor, 大学院・医学研究院, 助手 (40325444)

Co-Investigator(Kenkyū-buntansha) ICHIKI Toshihiro  Graduate School of Medical Sciences, Assistant Professor, 医学部附属病院, 助手 (80311843)
TSUSTUI Hiroyuki  Graduate School of Medical Sciences, Lecturer, 医学部附属病院, 講師 (70264017)
SHIMOKAWA Hiroaki  Graduate School of Medical Sciences, Assistant Professor, 大学院・医学研究院, 助教授 (00235681)
UTSUMI Hideo  Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究院, 教授 (20101694)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordsheart failure / cytokine / nitric oxide / reactive oxygen species / NF-kB / transgenic mice / 酸化窒素 / 活性酵素種
Research Abstract

We took advantage of transgenic mice with cardiac-specific overexpression of TNF-α(TG) to investigate the role of proinflammatory cytokines in the pathogenesis of congestive heart failure. Inhibition of iNOS improved β-adrenergic inotropic responsiveness in TG. However, crossing TG with iNOS knockout mice did not affect myocardial inflammation, ventricular hypertrophy, or the survival of TG, suggesting that NO-independent mechanisms might be more important in the process of cardiac remodeling. Myocardial production of hydroxyl radical detected by electron spin resonance spectroscopy was significantly increased in TG. In vitro studies indicated that intimate link between TNF-α, ROS, and mitochondria DNA damage might play an important role in myocardial remodeling and failure. Crossing TG with NF-kB (p50) knockout mice improved the survival of male TG, although it did not ameliorate myocardial inflammation. Thus, NF-kB might play an important role in myocardial hypertrophy and failure. ACE activity was increased in the myocardium of TG. These results indicated that we should focus on ROS and NF-kB to find new therapeutic strategies for congestive heart failure.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Funakoshi H, Kubota T, Machida Y, Kawamura N, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A.: "Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha"Am J Physiol Heart Circ Physiol.. 282. H2159-H2166 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Funakoshi H, Kubota T, Kawamura N, Machida Y, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A.: "Disruption of inducible nitric oxide synthase improves beta-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy"Circ Res.. 90. 959-965 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Machida Y, Kubota T, Kawamura N, Funakoshi H, Ide T, Utsumi H, Li YY, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A.: "Overexpression of tumor necrosis factor-alpha increases production of hydroxyl radical in murine myocardium"Am J Physiol Heart Circ Physiol.. 284. H449-H455 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suematsu N, Tsutsui H, Wen J, Kang D, Ikeuchi M, Ide T, Hayashidani S, Shiomi T, Kubota T, Hamasaki N, Takeshita A.: "Oxidative stress mediates tumor necrosis factor-alpha induced mitochondrial DNA damage and dysfunction in cardiac myocytes"Circulation. 107. 1418-1423 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Funakoshi H, Kubota T, Machida Y, Kawamura N, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A.: "Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha."Am J Physiol Heart Circ Physiol. 282. H2159-2166 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Funakoshi H, Kubota T, Kawamura N, Machida Y, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A.: "Disruption of inducible nitric oxide synthase improves beta-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy."Circ Res.. 90. 959-965 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Machida Y, Kubota T, Kawamura N, Funakoshi H, Ide T, Utsumi H, Li YY, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A.: "Overexpression of tumor necrosis factor-alpha increases production of hydroxyl radical in murine myocardium."Am J Physiol Heart Circ Physiol. 284. H449-H455 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suematsu N, Tsutsui H, Wen J, Kang D, Ikeuchi M, Ide T, Hayashidani S, Shiomi T, Kubota T, Hamasaki N, Takeshita A.: "Oxidative stress mediates tumor necrosis factor-alphainduced mitochondrial DNA damage and dysfunction in cardiac myocytes."Circulation. 107. 1418-1423 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Funakoshi H, Kubota T, Machida Y, Kawamura N, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A.: "Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha"Am J Physiol Heart Circ Physiol.. 282. H2159-H2166 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Funakoshi H, Kubota T, Kawamura N, Machida Y, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A.: "Disruption of inducible nitric oxide synthase improves beta-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy"Circ Res.. 90. 959-965 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Machida Y, Kubota T, Kawamura N, Funakoshi H, Ide T, Utsumi H, Li YY, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A.: "Overexpression of tumor necrosis factor-alpha increases production of hydroxyl radical in murine myocardium"Am J Physiol Heart Circ Physiol.. 284. H449-H455 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suematsu N, Tsutsui H, Wen J, Kang D, Ikeuchi M, Ide T, Hayashidani S, Shiomi T, Kubota T, Hamasaki N, Takeshita A.: "Oxidative stress mediates tumor necrosis factor-alpha induced mitochondrial DNA damage and dysfunction in cardiac myocytes"Circulation. (in press).

    • Related Report
      2002 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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