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2000 Fiscal Year Final Research Report Summary

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
KeywordseNOS gene / polymorphism RPA1 / microplate method / NOx / Nox
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.

  • Research Products

    (13 results)

All Other

All Publications (13 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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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

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Published: 2002-03-26  

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