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Human Molecular Genetics, 2000, Vol. 9, No. 18 2629-2637
© 2000 Oxford University Press

Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a –786T->C mutation associated with coronary spastic angina

Yoshihiro Miyamoto, Yoshihiko Saito+, Masafumi Nakayama1, Yukio Shimasaki1, Toshihiro Yoshimura2, Michihiro Yoshimura1, Masaki Harada, Noboru Kajiyama, Ichiro Kishimoto, Koichiro Kuwahara, Jun Hino3, Emiko Ogawa, Ichiro Hamanaka, Shigeki Kamitani, Nobuki Takahashi, Rika Kawakami, Kenji Kangawa3, Hirofumi Yasue1 and Kazuwa Nakao

Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyou-ku, Kyoto 606-8507, Japan, 1Department of Cardiovascular Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan, 2Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan and 3National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-0873, Japan

We recently reported that a mutation (–786T->C) in the promoter region of the endothelial nitric oxide synthase (eNOS) gene reduced transcription of the gene and was strongly associated with coronary spastic angina and myocardial infarction. 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, whereas, conversely, overexpression of RPA1 further reduced it. RPA1 was similarly detected in placenta and eNOS mRNA levels in placentas carrying the –786T->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 –786T->C mutation were significantly lower than among those without the mutation. RPA1 thus apparently functions as a repressor protein in the –786T->C mutation-related reduction of eNOS gene transcription associated with the development of coronary artery disease.

+ To whom correspondence should be addressed. Tel: +81 75 751 3180; Fax: +81 75 751 4351; Email: yssaito@kuhp.kyoto-u.ac.jp


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