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Exploration of the novel therapeutic methods for the treatment of chronic circulatory diseases

Research Project

Project/Area Number 11357019
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 応用薬理学・医療系薬学
Research InstitutionUniversity of Tsukuba

Principal Investigator

GOTO Katsutoshi  University of Tsukuba, Institute of Basic Medical Sciences, Professor, 基礎医学系, 教授 (30012660)

Co-Investigator(Kenkyū-buntansha) MIYAUCHI Takashi  University of Tsukuba, Institute of Basic Medical Sciences, Professor, 臨床医学系, 講師 (60222329)
MIWA Yoshihiro  University of Tsukuba, Institute of Basic Medical Sciences, Assistant Professor, 基礎医学系, 講師 (70263845)
SAKURAI Takeshi  University of Tsukuba, Institute of Basic Medical Sciences, Associate Professor, 基礎医学系, 助教授 (60251055)
MURATA Sakae  Insti. Drug Develop., Tanabe Pharmaceut. Comp. Chief, 循環薬理部, 部長
KASUYA Yoshitoshi  Grad.Sch. Med. Chiba Univ. Associate Professor, 大学院・医学研究科・高次機能系分子生体機構学, 助教授 (70221877)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥38,560,000 (Direct Cost: ¥35,200,000、Indirect Cost: ¥3,360,000)
Fiscal Year 2001: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
Fiscal Year 2000: ¥11,200,000 (Direct Cost: ¥11,200,000)
Fiscal Year 1999: ¥12,800,000 (Direct Cost: ¥12,800,000)
Keywordsendothelin / chronic circulatory disease / myocardial infarction / chronic heart failure / cardiac remodeling / cardiomyopathic hamster / ET receptor antagonist / HIF-1α / 心不全 / 受容体 / 受容体拮抗薬 / アポトーシス / ミトコンドリア / 動脈硬化 / upregulation / 心筋梗塞ラット / 変換酵素 / エンドセリン受容体 / 免疫組織化学
Research Abstract

The aim of this research project is to develop new therapeutic drugs for the treatment of chronic circulatory diseases e.g. chronic heart failure, pulmonary hypertension, etc., by paying special attention on the role of endothelin (ET) as an endogenous factor in the development, maintenance and aggravation of the diseases. For this purpose, various animal models of chronic circulatory diseases were utilized. In cardiac tissues of rats with chronic heart Mure due to coronary artery occlusion, the expression of ET-1 mRNA and the content of ET-1 peptide were significantly increased, and the expression of ET_A receptors was also elevated, indicating that the ET system was markedly enhanced in the failing heart. ETA receptor antagonist decreased the left ventricular +dp/dt/pmax in rats with myocardial infarction soon after coronary occlusion, suggesting that endogenous ET-1 is playing an important role for maintaining cardiac function at the acute phase. However, if the stimulation by ET-1 continues for a long period, the heart would gradually bear overload, thereby resulting in chronic heart, failure with marked hypertrophy 'and flbrosis, I.e. so-called cardiac remodeling. An identical phenomenon was also observed in hamster with cardiomyopathy, an animal model of non-ischemic heart failure. Impairment of cardiac metabolism by the inhibition of mitochondrial Respiratory pathway in cultured cardiomyocytes, an in vitro model of heart failure, ET-1 production was markedly enhanced via expression of HIF-1 α.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Kobayashi T: "Expression of endothlin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in falling rat heart"Am J Physiol.. 276. H1197-H1206 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi-Kono R.: "Role or endothelin in deterioration of heart failure due to cardiomyopathy in hamsters : increase in endothelin-1 production in the heart and beneficial effect of endothelin A receptor antagonist on survival and cardiac function"Circulation. 99. 2171-2176 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Abe Y.: "Subtype-specific trafficking of endothelin receptors"J Biol Chem.. 275. 8664-8671 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kakinuma Y.: "Novel molecular mechanisms of increased myocardial endothelin-1 expression in the falling heart involving the transcriptional factor hypoxia-inducible factor-1 alpha induced for impaired myocardial energy metabolism"Circulation. 103. 2387-2394 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yuki K: "Endothelin-1 production is enhanced by rotenone, a mitochondrial complex I inhibitor, in cultured rat myocytes"J Cardiovasc Pharmacol.. 38. 850-858 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Goto K.: "Basic and therapeutic relevance of endothelin-mediated regulation"Biol Pharm Bull. 24. 1219-1230 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Goto K.: "History of endothelin. in "Pulmonary Actions of Endothelins""Binkhauser Verlag, Basel/Switzerland. 1-20 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kobayashi T, Miyauchi T, Sakai S, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y: "Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart"Am J Physiol.. 276. H1197-H1206 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ueno M, Miyauchi T, Sakai S, Kobayashi T, Goto K, Yamaguchi I: "Effects of physiological or pathophysiological pressure load in vivo on myocardial expression of ET-1 and receptors"Am J Physiol.. 277. R1321-R1330 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kakinuma K, Miyauchi T, Kobayashi T, Yuki K, Maeda S, Sakai S, Goto K, Yamaguchi I: "Myocardial expression of endothelin-2 is altered reciprocally to that of endothelin-1 during ischemia of cardiomyocytes in vitro and during heart failure in vivo"Life Sci.. 65. 1671-1683 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi-Kono R, Miyauci T, Hoshina T, Kobayashi T, Aihara H, Sakai S, Yabana H, Goto K, Sugishita Y,Murata S: "Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters : increase in endothelin-1 production in the heart and beneficial effect of endothelin A receptor antagonist on survival and cardiac function"Circulation. 99. 2171-2176 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Abe Y, Nakayama K, Yamanaka A, Sakurai T, Goto K: "Super-specific trafficking of endothelin receptors"J Biol Chem.. 275. 8664-8671 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kakinuma Y, Miyauchi T, Yuki K, Murakosho N, Goto K, Yamaguchi I: "Novel molecular mechanisms of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-1 alpha induced for impaired myocardial energy metabolism"Circulation. 103. 2387-2394 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yuki K, Miyauchi T, Kakimuma Y, Murakoshi N, Maeda S, Goto K, Yamaguchi I: "Endothelin-1 production is enhanced by rotenone, a mitochondrial complex I inhibitor, in cultured rat cardiomyocytes"J Cardiovasc Pharmacol.. 38. 850-858 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Goto K: "History of endothelin"in "Pulmonary Actions of Endothelins" ed by Goldie RG & Hay DW, Birkhauser Verlag, Basel/Switzerland. 1-20 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miyauchi T, Goto K: "Heart failure and endothelin receptor antagoftists"Trends Pharmacol Sci. 20. 210-217 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Goto K: "Basic and therapeutic relevance of endothelin-mediated regulation"Biol Pharm Bull. 24. 1219-1230 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Goto K.: "Basic and therapeutic relevance of endothelin-mediated regulation"Biol Pharm Bull.. 24(11). 1219-1230 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yuhki Kl., Miyauchi T., Kakinuma Y., Murakoshi N., Maeda S., Goto K.: "Endothelin-1 production is enhanced by rotenone,a mitochondrial complex I inhibitor,in cultured rat cardiomyocytes"J Cardiovasc Pharmacol.. 38(6). 850-858 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kakinuma Y., Miyauchi T., Yuki K., Murakoshi N., Goto K., Yamaguchi I.: "Novel molecular mechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-1 alpha induced for impaired myocardial energy metabolism"Circulation. 103(19). 2387-2394 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Lazaratos S., Irukayama-Tomobe Y., Miyauchi T., Goto K., Nakahara A.: "Oxygen radicals mediate the final exacerbation of endothelin-1-induced gastric ulcer in rat"Eur J Pharmacol. 413(1). 121-129 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ogata T., Miyauchi T., Sakai S., Irukayama Y., Goto K., Yamaguchi I.: "Stimulation of peroxisome proliferator-activated receptor α (PPARα) attenuates cariac fibrosis and endothelin-1 production in pressure-overloaded rat hearts"Clin.Sci.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sakai S., Miyauchi T., Irukayama-Tomobe Y., Ogata T., Goto K., Yamaguchi I.: "Peroxisome proriferator-activated receptor-γ (PPARγ) activators inhibit endothelin-1-related cardiac hypertrophy in rats"Clin.Sci.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kakinuma,Y.: "Mitochondrial dysfunction of cardiomyocytes causing impairment of cellular energy metabolism induces apoptosis and concomitant increase in cardiac endothelin-1 expression"J.Cardiovasc Pharmacol.. 36(5Suppl 1). S201-S204 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yuki,K.: "Mitochondrial dysfunction increases expression of endothelin-1 and induces apotosis through caspase-3 activation in rat cardiomyocytes in vitro."J.Cardiovasc Pharmacol.. 36(5Suppl 1). S305-S310 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ueno,M.: "Endothelin-A-receptor antagonist and oral prostacyclin analog are comparably effective in ameliorating pulmonary hypertension and right ventricular hypertrophy in rats"J Cerdiovasc Phamacol.. 275(12). 8664-8671 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Abe,Y.: "Subtype-specific trafficking of endothelin receptors."J Biol Chem.. 275(12). 8664-8671 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Abe,Y: "Functional Analysis of Five Endothelin-B Receptor Mutations Found in Human Hischsprung Disease Patients"Biochem.And Biophys.Res.Commun.. 275. 524-531 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kobayashi,T.: "Corresponding distributions of increased endothelin-B receptor expression and increased endothelin-1 expression in the aorta of apolipoprotein E-deficient mice with advanced atherosclerosis."Pathol.Int.. 50(12). 929-936 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyauchi,T.: "Heart failure and endothelin receptor antagonists."Trends in Pharmacol.Sci.. 20. 210-217 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamauchi-Kohno,R.: "Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters."Circulation. 99. 2171-2176 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kobayashi,T.: "Expression of endothelin-1,ET_A and ET_B receptors,and ECE and distribution of endothelin-1 in failing rat heart."Am.J.Physiol.. 276. H1197-H1206 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ueno,M.: "Effects of physiological or pathological pressure load in vivo on myocardial expression of ET-1 and receptors."Am.J.Physiol.. 277. R1321-R1330 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kakinuma,Y.: "Myocardial expression of endothelin-2 is altered reciprocally to that of endothelin-1 during ischemia of cardiomyocytes in vitro and during heart failure in vivo."Life Sci.. 65. 1671-1683 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Asada,S.: "Cytodifferentiation potentiates aFGF-induced p21ras/Erk signaling pathway in rat cultured astrocytes."Biochem.Biophys.Res.Commun.. 260. 441-445 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Goto,K.: "History of Endothelin in "Pulmonary Actions of Endothelins""Birkhauser Verlag Basel/Switzerland. 20 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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