2000 Fiscal Year Final Research Report Summary
Molecular Mechanism for Coronary Spastic Angina as a Transcriptional Factor-Related Disease
| Project/Area Number |
11557053
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
SAITO Yoshihiko Kyoto University, Department of Medicine and Clinical Science, Associate Professor, 医学研究科, 助教授 (30250260)
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| 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)
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| Project Period (FY) |
1999 – 2000
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| Keywords | eNOS gene / polymorphism RPA1 / microplate method / NOx / Nox |
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| 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.
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[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
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[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)
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「研究成果報告書概要(欧文)」より
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[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
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[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
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[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
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[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
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[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)
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「研究成果報告書概要(欧文)」より
