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2005 Fiscal Year Final Research Report Summary

Identification of intracellular signaling molecules that bind to cardiac p300 during the development of heart failure and its application to pharmacological therapy

Research Project

Project/Area Number 16390230
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionClinical Research Institute, Kyoto Medical Center, National Hospital Organization

Principal Investigator

HASEGAWA Koji  Kyoto Medical Center, National Hospital Organization, Division of Translational Research, Director, )・展開医療研究部, 部長 (50283594)

Co-Investigator(Kenkyū-buntansha) KITA Toru  Kyoto University, Departmetn of Cardiovascular Medicine, Professor, 大学院・医学研究科, 循環器内科・教授 (60161460)
MORIMOTO Tatsuya  Research Institute for Production Development, Laboratory of Cardiovascular Molecular Cellular Biology, Chief, 心血管分子細胞生物学研究室, 主任研究員 (50390779)
Project Period (FY) 2004 – 2005
Keywordscardiac myocyte / transcription / p300 / heart failure
Research Abstract

Hypertrophic stimuli such as hypertension initiates a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and change the pattern of gene expression. The expression of endothelin-1 in cardiac myocytes is markedly induced following pressure overload during the transition from compensated hypertrophy to decompensated heart failure. Identification of nuclear pathways that lead to this induction will provide novel pharmacological targets for heart failure. One of E1A-associated proteins, p300 plays a critical role for the induction of endothelin-1 expression in cardiac myoytes, and serves as a coactivator of hypertrophy-responsive transcriptional factors such as MEF-2 and GATA-4. A p300 protein also possesses histone acetyltransferase (HAT) activity, and is involved in hypertrophic stimuli-induced acetylation and DNA binding of GATA-4 in cardiac myocytes. We have generated transgenic mice with cardiac-specific overexpression of either wild-type p300 or mutant p300 that lose its HAT activity, and found that p300-mediated acetylation of GATA-4 is required for pathological myocyte growth with decompensated heart failure in vivo. Recently, several compounds that inhibit p300-HAT activity in vitro and in culture have been reported. One of these is a natural compound, currcumin, which inhibits histone acetylation in cultured HeLa cells and repress p300-mediated chromatin transcription. This compound repressed PE-induced hypertrophic responses such as myofibrilar organization and increase in cell size, PE-induced transactivation of the cardiac fetal genes, and PE-induced increase in the DNA binding activity of GATA-4. Thus, we identified a pharmacological agent that targets nuclear pathways for pressure overload-signaling in cardiac myocytes, and could be applied for the treatment of hypertension-induced heart failure in vivo.

  • Research Products

    (8 results)

All 2006 2005 2004

All Journal Article (8 results)

  • [Journal Article] Histone acetyltransferase activity of p300 is required for the promotion of left ventricular remodeling following myocardial infarction in adult mice in vivo2006

    • Author(s)
      Miyamoto-S, Kawamura-T, Hasegawa-K et al.
    • Journal Title

      Circulation 113

      Pages: 679-690

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Histone acetyltranferase activity of p300 is required for the promotion of left ventricular remodeling following myocardial infarction in adult mice in vivo.2006

    • Author(s)
      Miyamoto S, Kawamura T, Morimoto T, Ono K, Wada H, Kawase Y, Matsumori A, Nishio R, Kita T, Hasegawa K.
    • Journal Title

      Circulation 113

      Pages: 679-690

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes.2005

    • Author(s)
      Kawamura-T, Ono-K, Hasegawa-K et al.
    • Journal Title

      Journal of Biological Chemistry 280

      Pages: 19682-19688

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes.2005

    • Author(s)
      Kawamura T, Ono K, Morimoto T, Wada H, Hirai M, Hidaka K, Morisaki T, Heike T, Nakahata T, Kita T, Hasegawa K.
    • Journal Title

      J Biol Chem 280

      Pages: 19682-19688

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Endothelin-l-dependent nuclear factor of activated T lymphocyte signaling associates with transcriptional coactivator p300 in the activation of the B cell leukemia-2 promoter in cardiac myocytes.2004

    • Author(s)
      Kawamura T, Ono K, Morimoto T et al.
    • Journal Title

      Circulation Research 94

      Pages: 1492-1499

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] FOG-2 competes with GATA-4 for a transcriptional coactivator p300 and represses hypertrophic responses in cardiac myocytes.2004

    • Author(s)
      Hirai M, Ono K, Morimoto T, et al.
    • Journal Title

      Journal of Biological Chemistry 279

      Pages: 37640-37650

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Endothelin-1-dependent nuclear factor of activated T lymphocyte signaling associates with transcriptional coactivator p300 in the activation of the B cell leukemia-2 promoter in cardiac myocytes.2004

    • Author(s)
      Kawamura T, Ono K, Morimoto T, Akao M, Iwai-Kanai E, Wada H, Sowa N, Kita T, Hasegawa K.
    • Journal Title

      Circ Res. 94

      Pages: 1492-1499

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] FOG-2 competes with GATA-4 for a transcriptional coactivator p300 and represses hypertrophic responses in cardiac myocytes.2004

    • Author(s)
      Hirai M, Ono K, Morimoto T, Kawamura T, Wada H, Kita T, Hasegawa K.
    • Journal Title

      J Biol Chem 279

      Pages: 37640-37650

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2007-12-13  

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