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Specific characters of apoptotic signal transduction in cardiomyocytes

Research Project

Project/Area Number 13670700
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

TAKEMURA Genzou  University Hospital, Internal Mecine II, Associate Professor, 医学部附属病院, 講師 (40283311)

Co-Investigator(Kenkyū-buntansha) FUJIWARA Hisayoshi  Graduate School of Medicine, Division of Cardiology, Professor, 大学院・医学研究科, 教授 (80115930)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥2,400,000 (Direct Cost: ¥2,400,000)
KeywordsApoptosis / Cardiomyocyte / Signal transduction / Fas / Fas ligand system / MAPK family / Ultrastructure
Research Abstract

Cultured neonatal mouse cardiomyocytes were treated with agonistic anti-Fas antibody (FA), AD, or both (FA + AD). In this system, apoptotic signals related with Fas-induced apoptotic pathways were examined by RT-PCR and immunoblottings. In addition, antisense oligonucleotide (AS) studies were performed. The treatment with FA+AD induced up-regulation of Fas, activation of c-Jun N-terminal kinase (JNK), which is one of the key molecules of the alternate pathway of Fas-induced apoptosis, up-regulation of Bax, up-regulation and activation of caspase-3, activation of caspase-3 dependent DNase (CAD), and final DNA fragmentation and apoptotic morphologies in cardiomyocytes. FA alone or AD alone did not affect any part of the above pathway. However, mRNA of mutagen-activated protein kinase phosphatase-1 (MKP-1), an in activator of JNK, was up-regulated by FA alone, but not by FA+AD or AD alone. Pretreatment with AS against MKP-1 induced apoptosis in FA alone-treated cardiomyocytes, whereas AS against JNK1 prevented apoptosis induced by FA+AD. On the other hand, FA+AD did not result in the activation of either caspase-8, one of the key molecules of the classic pathway in Fas-induced apoptosis, p38 MAPK, or extra cellular signal-regulated kinase (ERK). In conclusion, cardiomyocyte apoptosis by FA+AD depends on the alternate pathway through the JNK, Bax and caspase-3, and CAD-dependent pathways including a positive feedback mechanism of Fas up-regulation. The molecular mechanism that prevents Fas stimulation alone from inducing apoptosis involves up-regulation of MKP-1, an inhibitor of JNK; this up-regulation is inhibited by AD.

Report

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

    (6 results)

All Other

All Publications (6 results)

  • [Publications] Aoyama T, Takemura G, Maruyama M, et al.: "Molecular mechanisms of non-apoptosis by Fas stimulation alone versus apoptosis with an additional actinomycin D in cultured cardiomyocytes"Cardiovascular Research. 55. 787-798 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hayakawa K, Takemura G, Koda M, et al.: "Sensitivity to apoptosis signal, clearance rate, and ultrastructure of Fas ligand-induced apoptosis in in vivo adult cardiac cells"Circulation. 105. 3039-3045 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aoyama T, Takemura G, Maruyama R, Kosai K, Takahashi T, Koda M, Hayakawa K, Kawase Y, Minatoguchi S, Fujiwara H.: "Molecular mechanisms of non-apoptosis by Fas stimulation alone, versus apoptosis with an additional actinomycin D in cultured cardiomyocytes"Cardiovascular Research. 55(4). 787-798 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hayakawa K, Takemura G, Koda M, Kawase Y, Maruyama R, Li Y, Minatoguchi S, Fujiwara T, Fujiwara H: "Sensitivity to apoptosis signals, clearance rate, and ultrastructure of Fas ligand induced apoptosis in in vivo adult cardiac cells"Circulation. 105(25). 3039-3045 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aoyama T, Takemura G, Maruyama M et al.: "Molecular mechanisms of non-apoptosis by Fas stimulation alone versus apoptosis with an additional actinomycin D in cultured cardiomyocytes"Cardiovascular Research. 55・4. 787-798 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hayakawa K, Takemura G, Koda M et al.: "Sensitivity to apoptosis signal, clearance rate, and ultrastructure of fas ligand-induced apoptosis in in vivo adult cardiac cells"Circulation. 105・25. 3039-3045 (2002)

    • Related Report
      2002 Annual Research Report

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

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