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Role of Toll-like receptor in cardiovascular remodeling

Research Project

Project/Area Number 17590702
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

TAKEISHI Yasuchika  Yamagata University, Department of Cardiology, Pulmonology, and Nephrology, Associate Professor, 医学部, 助教授 (40272067)

Co-Investigator(Kenkyū-buntansha) GOTO Kaoru  Yamagata University, Department of Anatomy and Cell Biology, Professor, 医学部, 教授 (30234975)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordshypertrophy / remodeling / heart failure / cell signaling / diacylglycerol kinase / protein kinase C / G protein / myocardial infarction / myocardinal infarction / hypertophy
Research Abstract

Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DAG) and controls cellular DAG levels, thus acting as a negative regulator of protein kinase C (PKC) and subsequent cellular signaling. We previously reported DGK inhibited angiotensin II and phenylephrine-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy. Left ventricular-(LV) remodeling, including cardiomyocyte necrosis, scar formation, LV geometric changes, and cardiomyocyte hypertrophy, contributes to cardiac dysfunction and mortality after myocardial infarction (MI). Although precise cellular signaling mechanisms for LV remodeling are not fully elucidated, Gq protein-coupled receptor signaling pathway including DAG and PKC are involved in this process. We examined whether DGK modifies LV remodeling after MI. Left anterior descending coronary artery was ligated in transgenic mice with cardiac-specific overexpression of DGKζ (DGKζ-TG) and wild-type (WT) mice. LV chamber dilatation, reduction of L … More V systolic function, and increases in LV weight and lung weight at 4 weeks after MI were attenuated in DGKζ-TG mice compared to WT mice. In the non-infarct area, fibrosis fraction and up-regulation of profibrotic genes such as transforming growth factor-β1, collagen type I, and collagen type III were blocked in DGKζ-TG mice. The survival rate at 4 weeks after MI was higher in DGKζ-TG mice than in WT mice.
Thoracic transverse aortic constriction (TAC) was created in DGKζ-TG and WT mice. Increases in heart weight at 4 weeks after TAC were attenuated in DGKζ-TG mice compared to WT mice. Increases in inter-ventricular septal thickness, dilatation of the left ventricular cavity, and decreases in left ventricular systolic function were observed with echocardiography in WT mice at 4 weeks after TAC surgery. However, these structural and functional changes after TAC were attenuated in DGKζ-TG mice. In WT mice, cardiac fibrosis and up-regulation of profibrotic genes such as transforming growth factor-β1, collagen type I, and collagen type III were observed at 4 weeks after TAC. However cardiac fibrosis and gene induction of collagen type I and type III, but not transforming growth factor-βl, were blocked in DGKζ-TG mice.
These results demonstrate the first evidence that DGKζ suppresses LV structural remodeling and fibrosis and improves survival after MI. DGKζ also prevents pressure overload-induced cardiac hypertrophy. DGKζ may be a potential novel therapeutic target to prevent cardiac hypertrophy and progression to heart failure. Less

Report

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

    (19 results)

All 2007 2006 2005

All Journal Article (19 results)

  • [Journal Article] Diacylglycerol kinase ζ attenuates pressure overload-induced cardiac hypertrophy.2007

    • Author(s)
      Harada M, et al.
    • Journal Title

      Circ J 71

      Pages: 276-282

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Diacylglycerol kinase ζ attenuates left ventricular remodeling and improves survival after myocardial infarction.2007

    • Author(s)
      Niizeki T, et al.
    • Journal Title

      Am J Physiol Heart Circ Physiol 292

    • 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] Cardiac sympathetic denervation and ongoing myocardial damage for prognosis in heart failure.2007

    • Author(s)
      Arimoto T, et al.
    • Journal Title

      J Card Fail 13

      Pages: 34-41

    • 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] Diacylglycerol kinase ζ attenuates pressure overload-induced cardiac hypertrophy2007

    • Author(s)
      Harada M, Takeishi Y, Arimoto T, Niizeki T, Goto K, Walsh RA, Kubota I
    • Journal Title

      Circ J 71

      Pages: 276-282

    • NAID

      110006163616

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Diacylglycerol kinase ζ attenuates left ventricular remodeling and improves survival after myocardial2007

    • Author(s)
      Niizeki T, Takeishi Y, Arimoto T, Takahashi H, Shishido T, Koyama Y, Walsh RA, Goto K, Kubota I
    • Journal Title

      infarction. Am J Physiol Heart Circ Physiol 292

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Cardiac sympathetic denervation and ongoing myocardial damage for prognosis in heart failure.2007

    • Author(s)
      Arimoto T, Takeishi Y, Niizeki T, Okuyama H, Nozaki N, Hirono O, Watanabe T, Nitobe J, Tsunoda Y, Miyashita T, Takahashi H, Suzuki S, Koyama Y, Kitahara T, Okada A, Takahashi K, Kubota I
    • Journal Title

      J Card Fail 13

      Pages: 34-41

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Diacy1g1ycerol kinase ζ attenuates pressure overload-induced cardiac hypertrophy.2007

    • Author(s)
      Harada M, et al.
    • Journal Title

      Circ J 71

      Pages: 276-282

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury.2006

    • Author(s)
      Shishido T, et al.
    • Journal Title

      Biochem Biophys Res Commun 345

      Pages: 1446-1453

    • 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] Hyperuricemia is associated with high cardiac event rates in the elderly person with chronic heart failure.2006

    • Author(s)
      Niizeki T, et al.
    • Journal Title

      J Cardiol 47

      Pages: 219-228

    • 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] Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic myocardium.2006

    • Author(s)
      Itoh S, et al.
    • Journal Title

      Circulation 113

      Pages: 1787-1798

    • 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] Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic2006

    • Author(s)
      Itoh S, Ding B, Shishido T, Lerner-Marmarosh N, Wang N, Maekawa N, Berk BC, Takeishi Y, Yan C, Blaxall BC, Abe J
    • Journal Title

      myocardium. Circulation 113

      Pages: 1787-1798

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury2006

    • Author(s)
      Shishido T, Nozaki N, Takahashi H, Arimoto T, Niizeki T, Koyama Y, Abe JI, Takeishi Y, Kubota I
    • Journal Title

      Biochem Biophys Res Commun 345

      Pages: 1446-1453

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hyperuricemia is associated with high cardiac event rates in the elderly person with chronic heart failure.2006

    • Author(s)
      Niizeki T, Takeishi Y, Arimoto T, Okuyama H, Nozaki N, Hirono O, Tsunoda Y, Miyashita T, Takahashi H, Koyama Y, Shishido T, Kubota I
    • Journal Title

      J Cardiol 47

      Pages: 219-228

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Cardiac-specific overexpression of diacylglycerol kinase ζ prevents Gq protein coupled receptor agonists-induced cardiac hypertrophy in transgenic mice.2006

    • Author(s)
      Arimoto T, et al.
    • Journal Title

      Circulation 1113

      Pages: 60-66

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Adenovirus-mediated overexpression of diacylglycerol kinase ζ inhibits endothelia-1-induced cardiomyocyte hypertrophy.2005

    • Author(s)
      Takahashi H, et al.
    • Journal Title

      Circulation 111

      Pages: 1510-1516

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Ongoing myocardial damage relates to cardiac sympathetic nervous disintegrity in patients with heart failure.2005

    • Author(s)
      Arimoto T, et al.
    • Journal Title

      Ann Nucl Med 19

      Pages: 535-540

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Importance of pulmonary veins region for atrial tachycardia induction and maintenance in chronic volume overload-induced dilated atria.2005

    • Author(s)
      Hirose M, et al.
    • Journal Title

      J Cardiovasc Electrophysiol 16

      Pages: 760-769

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A combination of heart-type fatty acid binding protein and brain natriuretic peptide can reliably risk stratify patients hospitalized for chronic heart failure.2005

    • Author(s)
      Niizeki T, et al.
    • Journal Title

      Circ J 69

      Pages: 922-927

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Serum heart-type fatty acid binding protein predicts cardiac events in the elderly chronic heart failure patients.2005

    • Author(s)
      Niizeki T, et al.
    • Journal Title

      J Cardiol 46

      Pages: 9-15

    • Related Report
      2005 Annual Research Report

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

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