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New therapeutic approach for heart failure using HB-EGF mediated signal transduction

Research Project

Project/Area Number 17390229
Research Category

Grant-in-Aid for Scientific Research (B)

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

Principal Investigator

TAKASHIMA Seiji  Osaka University, Health Care Center, Assistant, 保健センター, 助手 (90379272)

Co-Investigator(Kenkyū-buntansha) KITAKAZE Masafumi  National Cardiovascular Center, Department of Clinical Research and Development, Director, 臨床研究開発部, 部長 (20294069)
HORI Masatsugu  Osaka University, Department of Cardiovascular Medicine, Professor, 医学系研究科, 教授 (20124779)
MINAMINO Tetsuo  Osaka University, Department of Cardiovascular Medicine, Assistant, 医学系研究科, 助手 (30379234)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2006: ¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 2005: ¥9,100,000 (Direct Cost: ¥9,100,000)
KeywordsHeart Failure / Growth Factor / drug discovery / contraction-excitation coupling / cardiotonic drug / zebrafish
Research Abstract

Dilated Cardiomyopathy is most important disease in cardiovascular field. In this research project, we focused on the identification of new therapeutic targets of heart failure. We established mice lacking growth factor HB-EGF. These mice suffered heart failure spontaneously and the pathological and physiological phenotypes are quite similar to these of human dilated cardiomyopahty. Using this animal model and human cases of cardiomyopaty, we examined the expression profile and screened out candidate genes which involved in the pathophysiology of heart failure. Among them we focused on the novel cardiac specific myosin light chain kinase named cardiac-MLCK This novel kinase was specifically expressed in heart and phsphorirates cardiac specific myosin light chain both in vivo and in vitro. Knock down of cardiac-MLCK in zebrafish caused sever impairment of cardiac development, suggesting its important role of cardiac development. Also in rat cultured cardiomyocytes, reducing expression of cardiac-MLCK caused impairment of cardiac sarcomere assembly. These data suggests that cardiac-MLCK is indispensable kinase of cardiac myosin light chain and essential for sarcomere assembly. Since MLCK expression was severely downregulated in cardiomyocyte in heart failure, reduced cardiac-MLCK may cause the insufficient sarcomere assembly resulting heart dysfunction. In fact the mutation of cardiac myosin light chain which is substrate of cardiac-MLCK is known to cause cardiomyopathy, indicating this substrate-kinase reaction is important for sarcomere assembly and its impairment causes cardiomyopathy. In conclusion we could successfully cloned out new therapeutic target of heart failure, cardiac-MLCK, using expression profiling of heart failure samples of model animal and human. Cardiac MLCK is potential target for cardiomyopathy. We are now screening other therapeutic targets using the same data base.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (13 results)

All 2007 2006 2005

All Journal Article (13 results)

  • [Journal Article] A Novel Cardiac Myosin Light Chain Kinase Regulates Sarcomere Assembly in the Vertebrate Heart2007

    • Author(s)
      Seguchi Osamu
    • Journal Title

      Journal of Clinical Investigation (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A Novel Cardiac Myosin Light Chain Kinase Regulates Sarcomere Assembly in the Vertebrate Heart.2007

    • Author(s)
      Osamu Seguchi, Seiji Takashima, Satoru Yamazaki, Masanori Asakura, Yoshihiro Asano, Yasunori Shintani, Masakatsu Wakeno, Tetsuo Minamino, Hiroya Kondo, Hidehiko Furukawa, Kenji Nakamaru, Asuka NaitoTomoko Takahashi, Toshiaki Ohtsuka, Koichi Kawakami, Tadashi Isomura, Soichiro Kitamura, Hitonobu Tomoike, Naoki Mochizuki, Masafumi Kitakaze
    • Journal Title

      J. of Clin.Invest. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.2006

    • Author(s)
      Shintani Yasunori
    • Journal Title

      EMBO J. 25・13

      Pages: 3045-3055

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats.2006

    • Author(s)
      Tsukamoto Osamu
    • Journal Title

      Cardiovasc Drugs Ther 20.2

      Pages: 93-102

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Long-term stimulation of adenosine A2b receptors begun after myocardial infarction prevents cardiac remodeling in rats.2006

    • Author(s)
      Wakeno Masakatsu
    • Journal Title

      Circulation 114・8

      Pages: 1923-1932

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.2006

    • Author(s)
      Shintani, Y., Takashima, S., Asano, Y., Kato, H., Liao, Y., Yamazaki, S., Tsukamoto, 0., Seguchi, O., Yamamoto, H., Fukushima, T., Sugahara, K., Kitakaze, M., Hori, M.
    • Journal Title

      Embo J 25

      Pages: 3045-55

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Long-term stimulation of adenosine A2b receptors begun after myocardial infarction prevents cardiac remodeling in rats.2006

    • Author(s)
      Wakeno, M., Minamino, T., Seguchi, O., Okazaki, H., Tsukamoto, O., Okada, K., Hirata, A., Fujita, M., Asanuma, H., Kim, J., Komamura, K., Takashima, S., Mochizuki, N., Kitakaze, M.
    • Journal Title

      Circulation. 114

      Pages: 1923-32

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats.2006

    • Author(s)
      Tsukamoto, O., Minamino, T., Sanada, S., Okada, K., Hirata, A., Fujita, M., Shintani, Y., Yulin, L., Asano, Y, Takashima, S., Yamasaki, S., Tomoike, H., Hori, M., Kitakaze, M.
    • Journal Title

      Cardiovasc Drugs Ther 20

      Pages: 93-102

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats.2006

    • Author(s)
      Tsukamoto Osamu
    • Journal Title

      Cardiovasc Drugs Ther 20・2

      Pages: 93-102

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Long-term stimulation of adenosine A2b receptors begun after myocardial infarction prevents cardiac remodeling in rats.2006

    • Author(s)
      Wakeno Masakatsu
    • Journal Title

      Circulation 114・18

      Pages: 1923-1932

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model.2005

    • Author(s)
      Li Yan
    • Journal Title

      Circulation 111

      Pages: 1672-1678

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Benidipine, a long-acting calcium channel blocker, inhibits cardiac remodeling in pressure-overloaded mice.2005

    • Author(s)
      Liao Yulin
    • Journal Title

      Cardiovascular Research 65

      Pages: 879-888

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Amlodipine ameliorates myocardial hypertrophy by inhibiting EGFR phosphorylation.2005

    • Author(s)
      Liao Yulin
    • Journal Title

      Biochei Biophys Res Commun 327

      Pages: 1083-1087

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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