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Molecular Mechanism for Coronary Spastic Angina as a Transcriptional Factor-Related Disease

Research Project

Project/Area Number 11557053
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field Circulatory organs internal medicine
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

SAITO Yoshihiko  Kyoto University, Department of Medicine and Clinical Science, Associate Professor, 医学研究科, 助教授 (30250260)

Co-Investigator(Kenkyū-buntansha) TERAOKA Hiroshi  Shionogi & Co., LTD.Diagnostic Science Divisio General Manager, 診断医学事業部, 部長(研究職)
YOSHIMURA Michihiro  Kumamoto University, Lecturer, 医学部・附属病院, 講師 (30264295)
OGAWA Yoshihiro  Kyoto University, Department of Medicine and Clinical Science, Assistant, 医学研究科, 助手 (70291424)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2000: ¥6,400,000 (Direct Cost: ¥6,400,000)
Fiscal Year 1999: ¥6,800,000 (Direct Cost: ¥6,800,000)
KeywordseNOS gene / polymorphism RPA1 / microplate method / NOx / Nox / NOx / 転写因子
Research Abstract

Cspastic angina is more frequently observed in Japanese than Caucasians. suggesting genctic risk factor is involved in its pathogenesis. In this context, we searched the polymorphisms in endothelial nitic oxide synthase (eNOS) gene, which are associated with coronary srastic angina. We found a missense mutation in exon 7 and a single nucletide polymorphism in the 5-flanking region of eNOS gene, T^<-786>→C Missense mutation in exon7 did not affect eNOS emzyme activity. but T^<-786>→C reduce eNOS gene transcription. To elucidate the molecular mechanism for the reduced eNOS gene transcription, we have now purified a protein that specifically binds to the mutant allele in nuclear extracts from HeLa cells. The purified protein was identical to replication protein A1 (RPA1), known as a single-stranded-DNA binding protein essential for DNA repair. replication and recombination. In human umbilical vein endothelial cells, inhibition of RPA1 expression using antisense oligonucleotide restored transcription driven by the mutated promoter sequence. while conversely, overexpression of RPA1 further reduced it. RPA1 was similarly detected in placenta. and eNOS mRNA levels in placentas carrying the T^<-786>→C mutation were significantly lower than in placentas without it. The functional importance of the diminished eNOS expression was revealed by the finding that serum nitrite/nitrate levels among individuals carrying the T^<-786>→C mutation were significantly lower than among those without the mutation. RPA1 thus apparently functions as a repressor protein in the T^<-786>→C mutation-related reduction of eNOS gene transcription associated with the development of coronary artery disease.

Report

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

    (25 results)

All Other

All Publications (25 results)

  • [Publications] I.Hamanaka: "Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 Is Involved in gpl30 Resistance in Cardiovascular System in Rat Treated with Cardiotrophin-1 (CT-1) in vivo."Circ.Res.. 88. 727-732 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] K.Kuwahara: "Neuron-Restrictive Silencer Element/Neuron-Restrictive Silencer Factor System Regulates Basal-and Endothelin-1-Inducible Atrial Natriuretic Peptide Gene Expression in Ventricular Myocytes"Mol Cell Biol.. 21. 2085-2097 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] N.Tamura: "Cardiac fibrosis in mice lacking brain natriuretic peptide."Proc.Natl.Acad.Sci.USA.. 97. 4239-4244 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Miyamoto: "Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a T-786→C mutation associated with coronary spastic angina."Hum.Mol.Genet.. 9. 2629-2637 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] K.Kuwahara: "Involvement of cardiotrophin-1 in cardiac myocyte-nonmyocyte interactions during hypertrophy of rat cardiac myocytes in vitro"Circulation. 100. 1116-1124 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Nakayama: "T-786→C mutation in the endothelial nitric oxide synthase gene is associated with coronary spasm : reduction in promoter activity."Circulation. 99. 2864-2870 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] I.Hamanaka, Y.Saito, H.Yasukawa, L.Kishimoto, K.Kuwahara, Y.Miyamoto, M.Harada, E.Ogawa, N.Kajiyama, N.Takahashi, T.Izumi, R.Kawakami, I.Masuda, A.Yoshimura, K.Nakao.: "Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 Is Involvedin gp130 Resistance in Cardiovascular System in Rat Treated with Cardiotrophin-1 (CT-1) in vivo."Cire.Res.. 88. 727-732 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] K.Kuwahara, Y.Saito, E.Ogawa, N.Takahashi, Y.Nakagawa, Y.Naruse, M.Harada, L.Hamanaka, T.Izumi, Y.Myamoto, I.Kishimoto, R.Kawakami, M.Nakanishi, N.Mori, K.Nakao.: "Neuron-Restrictive Silencer Element/Neuron-Restrictive Silencer Factor System Regulates Basal-and Endothe lin-1-Inducible Atrial Natriuretic Peptide Gene Expression in Ventricular Myocytes"Mol Cell Biol. 21. 2085-2097 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] N.Tamura, Y.Ogawa, H.Chusho, K.Nakamura, K.Nakao, M.Suda, M.Kasahara, R.Hashimoto, G.Katsuura, M.Mukoyama. H.Itoh, Y.Saito, I.Tanaka, H.Otani, M.Katsuki, K.Nakao.: "Cardiac fibrosis in mice lacking brain natriuretic peptide."Proc.Nail.Acad.Sci.USA. 97. 4239-4244 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] N.Tamura, Y.Ogawa, H.Chusho, K.Nakamura, K.Nakao, M.Suda, M.Kasahara, R.Hashimoto, G.Katsuura, M.Mukoyama. H.Itoh, Y.Saito, I.Tanaka, H.Otani, M.Katsuki, K.Nakao.: "Cardiac fibrosis in mice lacking brain natriuretic peptide."

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Miyamoto, Y.Saito, M.Nakayama, Y.Shimasaki, T.Yoshimura, M.Yoshimura, M.Harada, N.Kajiyama, L.Kishimoto, K.Kuwahara, J.Hino, E.Ogawa, I.Hamanaka, S.Kamitani, N.Takahashi, R.Kawakami, K.Kangawa, H.Yasue, K.Nakao.: "Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a T-786→C mutation associated with coronary spastic angina."Hum.Mol.Genet. 9. 2629-2637 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Nakayama, H.Yasue, M.Yoshimura, Y.Shimasaki, K.Kugiyama, S.Sugiyama, H.Sumida, H.Ogawa, Y.Saito, Y.Ogawa, Y.Miyamoto, K.Nakao.: "T-786→C mutation in the endothelial nitric oxide synthase gone is associated with coronary spasm : reduction in promoter activity."Circulation. 99. 2864-2870 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] K.Kuwahara, Y.Saito, M.Harada, M.Ishikawa, E.Ogawa, Y.Miyamoto, I.Hamanaka, S.Kamitani, N.Kajiyama, N.Takahashi, O.Nakagawa, I.Masuda, K.Nakao: "Involvement of cardiotrophin-1 in cardiac myocyte-nonmyocyte interactions during hypertrophy of rat cardiac myocytes in vitro"Circulation. 100. 1116-1124 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] K.Kuwahara: "Neuron-Restrictive Silencer Element/Neuron-Restrictive Silencer Factor System Regulates Basal-and Endothelin-1-Inducible Atrial Natriuretic Peptidc Gene Expression in Ventricular Myocytes "Mol Cell Biol.. 21. 2085-2097 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Mizuno: "Aldosterone Production is Activated in the Failing Ventricles in Humans."Circulation.. 103. 72-77 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] I.Hamanaka: "Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 Is Involved in gp130 Resistance in Cardiovascular System in Rat Treated with Cardiotrophin-1(CT- 1) in vivo."Circ.Res.. In press.. (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Kuwahara: "Cardiotorphin-1 phosphorylates Akt and BAD, and prolongs cell survival via a PI3K-dependent pathway in cardiac myocytes."J.Mol.Cell.Cardiol.. 32. 1385-1394 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] E.Ogawa: "Outside-in Signaling of Fibronectin Stimulates Cardiomyocyte Hypertrophy in Cultured Neonatal Rat Ventricular Myocytes"J.Mol.Cell Cardiol.. 32. 765-776 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Asai: "The Heart Is a Source of Circulating Cardiotrophin-1 in Humans"Biochem.Biophys.Res.Commun.. 279. 320-323 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] N.Tamura: "Cardiac fibrosis in mice lacking brain natriuretic peptide"Proc. Natl. Acad. Sci. USA. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] I.Hamanaka: "Effects of Cardiotrophin-1 on Hemodynamics and Endocrine Function of the Heart"Am. J. Physiol.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] E.Ogwa: "Outside-in Signaling of Fibronectin Stimulates Cardiomyocyte Hypertrophy in Cultured Neonatal Rat Ventricular Myocytes"J. Mol. Cell. Cardiaol. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] M.Nakayama: "T-786 C mutation in the endothelial nitric oxide synthase gene is associated with coronary spasm: reduction in promoter activity"Circulation. 99・22. 2864-2870 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K.Kuwahara: "Involvement of cardiotrophin-1 in cardiac myocyte-nonmyocyte interactions during hypertrophy of rat cardiac myocytes in vitro"Circulation. 100・10. 1116-1124 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K.Kuwahara: "The Effects of the selective ROCK inhibitor, Y27632, on ET-1-induced hypertrophic responses in neonatal rat cardiac myocytes -possible involvement of Rho/ROCK pathway in cardiac muscle cell hypertrophy-"FEBS Letters. 452・3. 314-318 (1999)

    • Related Report
      1999 Annual Research Report

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

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