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Elucidution of the Function of JAK-STAT Pathway Through gp130 in Cardiac Myocytes.

Research Project

Project/Area Number 10670650
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

KUNISADA Keita  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (80294057)

Co-Investigator(Kenkyū-buntansha) TAKIHARA Keiko  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70252640)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsSTAT3 / Transgenic mice / Doxorubicin / VEGF / JAK-STAT
Research Abstract

The signal transducer and activator of transcription (STAT) 3, a transcriptional factor downstream of several cytokines, is activated by Janus kinase (JAK) families and plays pivotal roles in cardiac hypertrophy through gp130. To determine the physiological significance of STAT3 in vivo, transgenic mice with cardiac-specific overexpression of the Stat3 gene (WT-TG) were generated. WT-TG manifested myocardial hypertrophy at 12 weeks of age with increased expression of the atrial natriuretic factor (ANF), β-myosin heavy chain (MHC) and cardiotrophin (CT) -1 genes. The animals were administered intraperitoneally with 15 mg/kg doxorubicin (Dox), an anti-neoplastic drug with restricted use because of its cardiotoxicity. The survival rates after 10 days were 25% (4/20) for control littermates (Cont), but 80% (16/20) for WT-TG (P<0.01). Dox administration significantly reduced the expression of the cardiac α-actin and Sat3 genes and increased the expression of ANF and β MHC genes which are in … More creased in cardiac heart failure in Cont hearts but not in WT-TG. These results provide direct evidence that STAT3 transduces not only hypertrophic signal but also protective signal against Dox-induced cardiomyopathy by inhibiting the reduction of cardiac contractile genes and the induction of cardiac protective factors.
Furthermore, activation of STAT3 induced by CT-1 increased the expression of vascular endothelial growth factor (VEGF)gene. In the WT-TG heart the VEGF gene is up-expressed, whereas in transgenic mice carrying dominant negative STAT3 gene it is down-expressed. These data reveal that STAT3 functions as a regulator of VEGF in the heart.
In summary STAT3 in the heart activated by IL-6, CT-1, which are known to be activated in the condition of congestive heart failure or ischemic heart disease, is concerned with the several self-defensive mechanisms through the production of angiogenic growth factor, cardiac protective factor, and the regulation of cardiac contractile protein Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] K. Kunisada, et al.: "Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes"Circulation. 98. 346-352 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H. Oh, et al: "Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytes"J. Biol. Chem.. 273. 9703-9710 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] E. Tone, et al.: "Angiotensin II interferes with leukemia inhibitory factor-induced STAT3 activation in cardiac myocytes"Biochem. Biophys. Res. Commun.. 253. 147-150 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H. Matsui, et al: "Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF) kappa B and NF-IL6 in cardiac myocytes"Cardiovasc Res. 42. 104-112 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Hishinuma, et al.: "Hypoxic stress induces cardiotrophin-1 expression in cardiac myocytes"Biochem. Biophys. Res. Commun.. 264. 436-440 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Kunisada, et al.: "Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy"Proc. Natl Acad Sci. USA. 97. 315-319 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Fujimoto, et al.: "Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes"J. Biol. Chem.. 276. 10561-10566 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kunisada, K., Tone, E., Fujio, Y., Yamauchi-Takihara, K., et al.: "Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes."Circulation. 98. 346-352 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Oh, H., Fujio, Y., Kunisada, K., Hirota, H., et al.: "Activation of phosphatidylinositol 3-kinase through glycoprotein130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytes."J Biol Chem. 273. 9703-9710 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ton, E., Kunisada, K., Fujio, Y., Matsui, H., et al.: "Angiotensin II interferes with leukemia inhibitory factor-induced STAT3 activation in cardiac myocytes."Biochem Biophys Res Commun. 253. 147-150 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Matsui, H., Ihara, Y., Fujio, Y., Kunisada, K., et al.: "Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-kappa B and NF-IL6 in cardiac myocytes."Cardiovasc Res. 42. 104-112 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hishinuma, S., Funamoto, M., Fujio, Y., Kunisada, K., et al.: "Hypoxic stress induces cardiotrophin-1 expression in cardiac myocytes"Biochem Biophys Res Commun. 264. 436-440 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kunisada, K., Negoro, S., Tone, E., Funamoto, M., et al.: "Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy."Proc Natl Acad Sci U S A. 97. 315-319 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Funamoto, M., Fujio, Y., Kunisada, K., Negoro, S., et al.: "Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes."J Biol Chem. 276. 10561-10566 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K.Kunisada: "Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes"Circulation. 98. 346-352 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] H.Oh: "Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytes"J Biol Chem. 273. 9703-9710 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] E.Tone: "Angiotensin II interferes with leukemia inhibitory factor-induced STAT3 activation in cardiac myocytes"Biochem Biophys Res Commun. 253. 147-150 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] H.Matsui: "Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-kappa B and NF-IL6 in cardiac myocytes"Cardiovasc Res. 42. 104-112 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S.Hishinuma: "Hypoxic stress induces cardiotrophin-1 expression in cardiac myocytes"Biochem Biophys Res Commun. 264. 436-440 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K.Kunisada: "Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy"Proc Natl Acad Sci USA. 97. 315-319 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] M.Funamoto: "Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes"J Biol Chem. (in press).

    • Related Report
      1999 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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