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FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injury.

Research Project

Project/Area Number 14370408
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Thoracic surgery
Research InstitutionMie University

Principal Investigator

YADA Isao  Mie University, Faculty of medicine, Professor, 医学部, 教授 (80093152)

Co-Investigator(Kenkyū-buntansha) TAKAO Motoshi  Mie University, Faculty of medicine, Research Associate, 医学部, 助手 (30263007)
ONODA Koji  Mie University, Hospital, Assistant Professor, 医学部附属病院, 講師 (70260601)
SHIMPO Hideto  Mie University, Faculty of medicine, Associate Professor, 医学部, 助教授 (70179076)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥8,200,000 (Direct Cost: ¥8,200,000)
Fiscal Year 2003: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2002: ¥5,500,000 (Direct Cost: ¥5,500,000)
Keywordsischemia-reperfusion injury / toll-like receptor 4 / extracellular signal-regulated kinase / mitogen-activated protein kinase / activating transcription factor-2 / inflammatory cytokines / toll-like receptor 4 / mitogen-activatted protein kinase / 細胞内シグラル伝達機構
Research Abstract

P38 mitogen-activated protein kinase (MAPK) is activated during myocardial ischemia-reperfusion (MI/R) injury. we examined the effect of a highly specific inhibitor of p38 MAPK, FR167653, in an experimental model of regional MI/R.
<Method> : CD-1 mice received Fr167653 intraperitoneally 24 hours prior to 30 minutes of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. P38 MAPK activation and kinase activity were determined by Western blotting with monoclonal antibodies for the phosphorylated from of p38 MAPK or its substrate, activating transcription factor -2. Nuclear factor (NF) -kB activity was measured by detecting translocation of NF-kB to the nucleus. The expression of inframmatory cytokines was measured by ribonuclease protection assay.
<Results> : Pretreatment of mice with FR167653 before MI/R resulted in reduction in p38 MAPK phosphorylation (p=.018), inhibition of p38 MAPK activity (p.047), less nulear of NF-kB(P=.001), and a decrease in the expression of inflammatory cytokiness (tumor necrosis factor-a : p=.023, ;interleukine01b : p=.038 ; mynocyte chemotacic protein-1 : p=.001) in the heart and the development of a significantly smaller infarct(p=.0069), when comared to hearts from mice trasted with vehicle aone. Activation of c-Jun NH2-terminal kinase and extracellular signa-regulated kinase were observed after MI/R, while not inhibited by FR167653
<Conclusion> : we conclude that FR167653 selectively inhibits p38 MAPK activation and activity during regional MI/R injury and efficaciously reduces infarct size (by 73.6%). Thus, p38 MAPK inhibition may have a role in the treatment of MI/R

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Shimamoto A, et al.: "HSP70.1 and -70.3 are required for late-phase protection induced by ischemic preconditioning of mouse hearts."American Journal of Physiology : Heart and Circulatory Physiology. 285. H866-H874 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A, et al.: "Microvascular responses to cardiopulmonary bypass."Seminars in Cardiothoracic and Vascular Anesthesia. 7・3. 333 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A, et al.: "Can donor heart endothelial activation be controlled?"Journal of Heart and Lung Transplantation. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A, Yada I, et al.: "FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injuly."The Journal of Thoracic and Cardiovascular Surgery. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A, et al.: "Toll-like receptor 4 (TLR4) mediates ischemia-reperfusion injury of the heart."The Journal of Thoracic and Cardiovascular Surgery. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A, et al.: "HSP70.1 and -70.3 are required for late-phase protection induced by ischemic preconditioning of mouse hearts."American Journal of Physiology : Hearts and Circulatory Physiology. 285. H866-H874 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A, et al.: "Microvascular responses to cardiopulmonary bypass."Seminars in Cardiothoracic and vascular anesthesia. 7-3. 333 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A.et al.: "Can donor heart endothelial activation be controlled?"Journal of Heart and Lung Transplantation. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A, Yada I, et al.: "FR167653 diminishes infarct size In a murine model of myocardial ischemia-reperfusion injury."The Journal of Thoracic and Cardiovascular Surgery. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A, et al.: "Toll-like receptor4(TLR4) mediates ischemia-reperfusion injury of the heart."The Journal of Thoracic and Cardiovascular Surgery. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimamoto A, et al.: "HSP70.1 and -70.3 are required for late-phase protection induced by ischemic preconditioning of mouse hearts"American Journal of Physiology : Heart and Circulatory Physiology. 285. H866-H874 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimamoto A, et al.: "Microvascular responses to cardiopulmonary bypass"Seminars in Cardiothoracic and Vascular Anesthesia. 7・3. 333 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimamoto A, et al.: "Can donor heart endothelial activation be controlled?"Journal of Heart and Lung Transplantation. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimamoto A, yada I, et al.: "FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injury"The Journal of Thoracic and Cardiovascular Surgery. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimamoto A, et al.: "Toll-like receptor 4(TLR4)mediates ischemia-reperfusion injury of the heart"The Journal of Thoracic and Cardiovascular Surgery. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimamoto A, et al.: "Specific Inhibition of p38 Mitogen-Activated Protein Kinase with FR167653 Attenuates Myocardial Ischemia-Reperfusion Injury in Mice"American Journal of Physiology : Heart and Circulatory Physiology. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimamoto A, et al.: "Microvascular responses to cardiopulmonary bypass"Seminars in Cardiothoracic and Vascular Anesthesia. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimamoto A, et al.: "Can donor heart endothelial activation be controlled?"Journal of Heart and Lung Transplantation. (in press). (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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