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Cardio-Specific Gene Expression and Genetic Analysis of Myocardial Disorders

Research Project

Project/Area Number 05304032
Research Category

Grant-in-Aid for Co-operative Research (A)

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionUniversity of Tokyo

Principal Investigator

YAZAKI Yoshio  Faculty of Medicine, University of Tokyo, Third Department of Internal Medicine, Professor, 医学部(病), 教授 (20101090)

Co-Investigator(Kenkyū-buntansha) NAGAI Ryozo  Faculty of Medicine, University of Tokyo, Third Department of Internal Medicine,, 医学部(病), 助教授 (60207975)
HIRAOKA Masakazu  Medical Research Institute, Tokyo Medical and Dental University, Department of C, 教授 (80014281)
NAKAO Kazuwa  Faculty of Medicine, University of Kyoto, Second Department of Internal Medicine, 医学部(病), 教授 (00172263)
TADA Michihiko  Faculty of Medicine, University of Osaka, First Department of Internal Medicine,, 医学部(病), 教授 (90093434)
SASAYAMA Shigetake  Faculty of Medicine, University of Kyoto, Third Department of Internal Medicine,, 医学部(病), 教授 (70109007)
木村 彰方  九州大学, 生医研, 助教授 (60161551)
松原 弘明  関西医科大学, 医学部(病), 助手 (10239072)
川口 秀明  北海道大学, 医学部(病), 講師 (70161297)
Project Period (FY) 1993 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥17,500,000 (Direct Cost: ¥17,500,000)
Fiscal Year 1994: ¥8,100,000 (Direct Cost: ¥8,100,000)
Fiscal Year 1993: ¥9,400,000 (Direct Cost: ¥9,400,000)
Keywordscardio-specific gene expression / cardiac hypertrophy / mechanism of transcriptional regulation / homeobox gene / hypertvophic cardiomyopathy / mitochondrial cardiomyopathy / dilated cardiomyopathy / long QT syndrome / 心筋細胞 / 遺伝子発現 / 心不全 / 心筋症 / BNP / カリウムチャンネル / アンギオテンシン / ミトコンドリア
Research Abstract

(A) Mechanisms of Cardio-Specific Regulation of the Genes Important to cardiac Functions
As for the mechanisms of cardiac hypertrophy, we showed using an in vitro stretch-model of cultured cardiac myocytes that the intracellular signaling cascades involving MAP kinase is, at least in part, mediated by myocardial angiotensin II and that myocardial renin-angiotensin system causes hypertrophy of cardiac myocytes and interstitial fibrosis. We also clarified the mechanisms regulating the expression and transcription of cardiac genes such as cytokine (IL-6), hormones (ANP,BNP,renin, angiotensin), potassium channel, and calcium pump in response to ischemia, mechanical load, calcium, and thyroid hormone. Furthermore, we isolated the human Csx gene using the murine Csx (cardio-specific homeobox) gene as a probe and found that the amino acid sequences of human and murine Csx genes are very similar, indicating that Csx gene is highly conserved among the species.
(B) Analysis of the Genes Responsible for Myocardial Disorders
Fourteen missense mutations of the cardiac beta-myosin heavy chain gene were detected in Japanese patients with hypertrophic cardiomyopathy (HCM), and 13 out of these 14 mutations were different from those found in Caucasian patients. In 11 out of 47 affected Japanese families, there was no linkage to cardiac beta-myosin heavy chain gene, indicating the genetic heterogeneity of Japanese patients with HCM.We also identified a point mutation in tRNA-Leu gene and deletions of mitochondrial DNA in patients with mitochondrial cardiomyopathy who had cardic hypertrophy. Furthermore, we found linkage of Japanese dilated cardiomyopathy to HLA-DR locus, and Japanese long QT syndrome (Romano-Ward syndrome) to HRAS and D11S922 loci on chromosome 11p15.5.

Report

(3 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Nishi,H.et al.: "Genetic analysis ofdilated Cardiomyopathy-HLA and Immunoglobulin genesmay confer susceotibility" Jpn Circ J. 56. 1054-1061 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Matsubara,H.et al.: "Shaker-related potassium channel.Kvl.4,mRNA regalation in cultur rat heart myochtes and differential exprssion." J Clin Invest.92. 1659-1666 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Ozawa,T.et al: "Mitochondrial DNA mutation and Survival rate." Lancet.345. 189 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nishi,H.et al: "Possible gene dose effect of a mutatn cardiac β-myosin heavy chain gene on the clinical expression of hypertrophic Cordiomyopathy." Biochem.Biophys.Res.Commum.200. 549-556 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Shiojima.I.et al.: "Assignment of cardiac homeobox gene CSX in human chromosome 5934." Genomics,in press.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Ogawa.Y,et al.: "Molucular cloning of the cDNA and gene encoding mouse brain natriuretic peptide and generation of transgonic mice..." J.Clin.Invest.93. 1911-1921 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Imanishi,T.et al.: "HLA,vol.1(Tsuji,K.ed.)" Oxford University Press, 155 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kimura,A.et al.: "Disease(Clark,E.8.ed.)" Futura Press, 7 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nishi H,et al.: "Genetic analysis of dilated cardiomyopathy-HLA and immunoglobulin genes may confer susceptibility" J Circ J. 56. 1054-1061 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Matsubara H,et al.: "Shaker-related potassium channel, Kv1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy" J Clin Invest. 92. 1659-1666 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Ozawa, T,et al.: "Mitochondrial DNA mutations and survival rate" Lancet. 345. 189 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nishi H,et al.: "Possible gene dose effect of a mutant cardiac b-myosin heavy chain gene on the clinical expression of hypertrophic cardiomyopathy." Biochem Biophys Res Commun. 200. 549-556 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Shiojima I,et al.: "Assignment of cardiac homeobox gene CSX to human chromosome 5q34" Genomics. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Ogawa Y,et al.: "Molecular cloning of the cDNA and gene encoding mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene" J Clin Invest. 93. 1911-1921 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nishi,H.et al.: "Genetic analysis of dilated Cardiomyopathy-HLA and immanoglobulin genes may confer susccptibility" Jpn Circ J. 56. 1054-1061 (1992)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsubara,H.et al.: "Shaker-related potassium channel,Kv1.4,mRNA regulation in cultur rat neart myocytes and differential expression...." J Clin Invest,. 92. 1659-1666 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ozawa,T,et al.: "Mitochondrial DNA mutation and survival rate." Lancet. 345. 189 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Nishi,H.et al.: "Possible gene close effect of a mutatn cardiac β-myosin heavy chain gene on the clinical expression of hypertrophic cardiomyopathy." Biochen.Biophys.Res.Commum.200. 549-556 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Shiojima,I.et al.: "Assignment of cardiac homeobox gene CSX to human chromosome 5g34" Genomics.(in press).

    • Related Report
      1994 Annual Research Report
  • [Publications] Ogawa,I.et al.: "Mducular cloning of the cDNA and gene encoding mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain..." J.Clin.Invest.93. 1911-1921 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Imanishi,T.et al.: "HLA,vol.1(Tsuji K.ed.)" Oxford University Press, 155 (1992)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kimura,A.et al.: "Disease(Clark E.B,ed.)" Futura Press., 7 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hiroaki Matsubara: "Shaker-related potassium channel Kv1.4,mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy." J.Clin.Inrest. 92. 1659-1666 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hideaki Kawaguchi: "Phosphatidylinositol Metabolism in Hypertrophic Rat Heart" Circulation Research. 72. 966-972 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 西宏文,古賀義則: "遺伝学ならびに分子生物学からみた心筋症" 日本内科学会雑誌. 82. 178-182 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Sato W,Sugiyama S: "Deletion of mitochondorial DNA in a patient with conduction block" Am.Heart J.125. 550-552 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Keiko Yamauchi-Takihara: "Hypoxic Stress Induces Caediac Hyocyte-derived Interleukin-6" J.Clin.Invest.(Submitted).

    • Related Report
      1993 Annual Research Report
  • [Publications] Kojima M,Nagai R: "Angiotensin II receptor antagonist TCV 116 reyresses hypertepsive left ventricular hypertrophy in vivo and inhibits intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro." Circulation. (in press).

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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