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2002 Fiscal Year Final Research Report Summary

Molecntan biological and pharmaco-physiological approach to pathophysiological roles of endothelin-1 in aggrarating heart failure

Research Project

Project/Area Number 12470147
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionUniversity of Tsukuba

Principal Investigator

MIYAUCHI Takashi  University of Tsukuba, Professon of Institute of Clinical Medicine, 教授 (60222329)

Co-Investigator(Kenkyū-buntansha) GOTO Katsutoshi  University of Tsukuba, Professon of Institute of Basic Medical Sciences, 教授 (30012660)
SAKURAI Takeshi  University of Tsukuba, Associate Professon of Institute of Basic Medical Sciences, 助教授 (60251055)
Project Period (FY) 2000 – 2002
Keywordsheart failare / endothelin / antagonist / pharmacology / phtsiology / mclesular biology / gene expression / cardiac hypeitrsphy
Research Abstract

In the present study, we studied the pathophysiological roles of endothelin-1 (ET-1) in heart failure by molecular biological and pharmaco-physiological approach. ET-1 induces myocardial hypertrophy and causes cellular injury in cardiac myocytes. The production of ET-1 is markedly increased in the failing heart and chronic treatment with an ET receptor antagonist greatly improves the survival rate of animals with CHF. An ET antagonist improves the alteration in the expression of various cardiac genes of classic molecular markers (eg, mRNA in ANP and 13 -myosin heavy chain) and of functional molecular markers (eg, mRNA levels of ryanodine receptor, sarcoplasmic reticulum calcium-ATPase) in the failing heart, suggesting that the great improvement of survival in CHF animals by an ET antagonist is partly attributed to the prevention of molecular changes in the failing heart. Several molecular mechanisms are considered to be involved in the marked increase in ET-1 expression in the failing heart. The transcription of the ET-1 gene is regulated through the phorbol-ester-sensitive c-fos and c-jun complexes, binding sites for nuclear factor-1, AP-1, and GATA proteins. In the failing heart, principal ATP generation by mitochondrial β-oxidation is impaired and adaptively switched to glycolysis. Hypoxia-inducible factor (HIF)-1α is an important transcriptional factor which activates gene expression of glycolytic enzymes. We find a HIF-1α binding site in 5'-regulatory region of ET-1 gene. Our data revealed a novel molecular mechanism of up-regulation of cardiac ET-1 in heart failure that the impairment of cardiac energy metabolism is involved in a marked increase in ET-1 expression through a transcriptional activation by HIF-1α. We also revealed that ET-1 induced cardiac hypertrophy is inhibited by activation of PPAR a partly via c-Jun NH2-terminal-kinase pathway. The present study showed that ET-1 plays important roles in worsening heart failure.

  • Research Products

    (14 results)

All 2002 2001

All Journal Article (13 results) Book (1 results)

  • [Journal Article] A combination of oral endothelin-A receptor antagonist and oral prostacyclin analogue is superior to each drug alone in ameliorating pulmonary hypertension in rats2002

    • Author(s)
      Ueno M, Miyauchi T, et al.
    • Journal Title

      Journal of the American College of Cardiology vol 40

      Pages: 175-181

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Vascular endothelin-B recepton system in vivo plays a favahable inhibitory role in vascular remodeling after injury revealed by endothelin-B receptor Knockoutmice2002

    • Author(s)
      Murakoshi N, Miyauchi T, et al.
    • Journal Title

      Circulation vol.106

      Pages: 1991-1998

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Involvement of endogenour endothelin-1 in exercise-induced redistribution of tissue blood flow : An endothelin receptor antagonist reduces the redistribatier2002

    • Author(s)
      Maeda S, Miyauchi T, et al.
    • Journal Title

      Circulation vol.106

      Pages: 2188-2193

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A combination of oral endothelin-A receptor antagonist and oral prostacyclin analogue is superior to each drug alone in ameliorating pulmonary hypertension in rats2002

    • Author(s)
      Ueno M, Miyauchi T, Sakai S, Yamauchi-Kohno R, Goto K, Yamaguchi I
    • Journal Title

      Journal of the American College of Cardiology 40(1)

      Pages: 175-181

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Vascular endothelin-B receptor system in vivo plays a favorable inhibitory role in vascular remodeling after injury revealed by endothelin-B receptor-knockout mice.2002

    • Author(s)
      Murakoshi N, Miyauchi T, Kakinuma Y, Ohuchi T, Goto K, Yanagisawa M, Yamaguchi I
    • Journal Title

      Circulation 106(15)

      Pages: 1991-1998

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Involvement of endogenous endothelin-1 in exercise-induced redistribution of tissue blood flow An endothelin receptor antagonist reduces the redistribution.2002

    • Author(s)
      Maeda S, Miyauchi T, Iemitsu M, Tanabe T, Irukayama-Tomobe Y, Goto K, Yamaguchi I, Matsuda M
    • Journal Title

      Circulation 106(17)

      Pages: 2188-2193

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training.2002

    • Author(s)
      Iemitsu M, Miyauchi T, Maeda S, Tanabe T, Takanashi M, Irukayama-Tomobe Y, Sakai S, Ohmori H, Matsuda M, Yamaguchi I
    • Journal Title

      American Journal of Physiology 283(5)

      Pages: H1750-H1760

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A novel pharmacological action of ET-1 to prevent the cytotoxicity of doxorubicin in cardiom yocytes2001

    • Author(s)
      Suzuki T, Miyauchi T.
    • Journal Title

      American Journal of Physiology vol280

      Pages: R1399-R1406

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Novel molecular mechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-indacible factor-1α induced for impaired myocardical enargy metabolism2001

    • Author(s)
      Kakinuma Y, Miyanchi T, et al.
    • Journal Title

      Circulation vol 103

      Pages: 2387-2394

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat2001

    • Author(s)
      Iemitsu M, Miyauchi T, et. al.
    • Journal Title

      American Journal of Physiology vol. 281

      Pages: R2029-R2036

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A novel pharmacological action of ET-1 to prevent the cytotoxicity of doxorubicin in cardiomyocytes.2001

    • Author(s)
      Suzuki T, Miyauchi T
    • Journal Title

      American Journal of Physiology 280

      Pages: R1399-R1406

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Novel molecular mechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-1α induced for impaired myocardial energy metabolism.2001

    • Author(s)
      Kakinuma Y, Miyauchi T, Yuki K, Murakoshi N, Goto K, Yamguchi I
    • Journal Title

      Circulation 103(19)

      Pages: 2387-2394

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Physiological and pathological cardiac hypertrophy induce different nalecular phenotypes in the rat.2001

    • Author(s)
      Iemitsu M, Miyauchi T, Maeda S, Sakai S, Kobayashi T, Fujii N, Miyazaki H, Matsuda M, Yamaguchi I
    • Journal Title

      American Journal of Physiology 281(6)

      Pages: R2029-2036

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] Annual Review 2002循環器2002

    • Author(s)
      酒井俊, 宮内卓
    • Total Pages
      282
    • Publisher
      中外医学社(編集者:杉下靖郎,門間和夫,矢崎義雄,高本眞一)
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2011-06-18  

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