Genetic analysis of endothelial nitric oxide synthase in patients with coronary spastic angina

冠状动脉痉挛性心绞痛患者内皮型一氧化氮合酶基因分析

基本信息

批准号：
09670732
负责人：
YOSHIMURA Michihiro
金额：
$ 2.24万
依托单位：
Department of Cardiovascular Medicine, Kumamoto University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

In pathophysiological research of coronary spasm, we have recently reported that nitric oxide (NO) activity is deficient in the coronary arteries of patients with coronary spasm. By genetic analysis of the endothelial nitric oxide synthase (eNOS), we have reported a missense Glu298Asp variant in the coding region and 3 linked variants, T-786*C A-922*G and T-1468*A, in the 5'-flanking region of the eNOS gene in patients with coronary spasm. The variants are significantly associated with coronary spasm.We are now examining whether the eNOS gene variants themselves exert an influence on the synthesis or the activity of eNOS.Our recent in vitro study has reveled that only the T-786*C variant in the 5'-flanking region reduces the promoter activity of the eNOS gene by using luciferase reporter gene assay. Also, our in vivo analysis revealed that the coronary diameter changes evoked by intracoronary injection of acetylcholine or nitroglycerin was greater in patients with the variant type allele than in those with the wild type allele. This accumulated evidence revealed that the T-786*C variant could be thought of as a functional mutation of coronary spasm.Just recently, we have reported that the eNOS gene variants are associated with other cardiovascular diseases such as myocardial infarction and essential hypertension.Thus, the series of studies about the eNOS gene variants may bring a new understanding of the pathophysiology of not only coronary spasm but also of other common cardiovascular diseases.

在冠状动脉痉挛的病理生理研究中，我们最近报道说，一氧化氮活性在冠状动脉痉挛患者的冠状动脉中缺乏。通过对内皮一氧化氮合酶（ENOS）的遗传分析，我们报告了编码区域中的错义GLU298ASP变体，3个连接的变体T-786*C A-922*G和T-1468*A，在5'冠状痉挛患者的eNOS基因的频率区域。这些变体与冠状动脉水疗中心显着相关。我们现在正在研究eNOS基因变体本身是否对eNOS的合成或活性产生影响。 ' - 频率区域通过使用荧光素酶报告基因测定法可以降低eNOS基因的启动子活性。同样，我们的体内分析表明，与患有野生型等位基因的患者相比，具有变异类型等位基因的患者乙酰胆碱或硝酸甘油的冠状直径变化更大。这一积累的证据表明，T-786*C变体可以被认为是冠状动脉曲折的功能突变。恰恰是我们报道，eNOS基因变体与其他心血管疾病（如心肌梗死和必需的高血压）有关，有关eNOS基因变异的一系列研究可能会给不仅对冠状动脉痉挛的病理生理学以及其他常见的心血管疾病的病理生理学有了新的了解。