Pathogenesis of coronary artery spasm : a study from the viewpoint of NO

冠状动脉痉挛的发病机制：从NO的角度研究

• 批准号: 08407019
• 负责人: TASUE Hirofumi
• 金额: $ 12.22万
• 依托单位: KUMAMOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08407019/
• 关键词: coronary spasm; angina pectoris; nitric oxide synthase; mutation; cigarette smoking; risk factor; polymorphism; transcrption factor; 一酸化窒素合成酵素; 遺伝子解析; 冠動脈

In pathophysiological research of coronary spasm, we have recently reportedthat nitric oxide (NO) activity is deficient in the coronary arteries of patients with coronary spasm. This conclusion was obtained by intracoronary injection of LNMMA, an inhibitor of nitric oxide synthase (NOS), during cardiac catheterization.Coronary spasm was mare prevalent in the Japanese than in Caucasian, suggesting that the genetic factor be involved in its pathogenesis. By genetic analysis of the endothelial nitric oxide synthase (eNOS), we have found 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. This finding shows the existence of the genetic factors in coronary spasm. However, it should be empathized that an environmental factors, such as cigarette smoking, is also an important risk factor for coronary spasm. … More 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. Less

在冠状动脉痉挛的病理生理学研究中，我们最近证实冠状动脉痉挛患者冠状动脉内一氧化氮（NO）活性缺乏。这一结论是通过在心导管术中冠状动脉内注射一氧化氮合酶（NOS）抑制剂LNMMA而获得的。日本人冠状动脉痉挛的发生率高于高加索人，提示遗传因素参与了其发病机制。通过对冠状动脉痉挛患者内皮型一氧化氮合酶（eNOS）基因的遗传学分析，发现eNOS基因编码区存在一个错义突变Glu 298 Asp，5 '侧翼区存在3个连锁突变T-786* CA-922*G和T-1468*A。这些变异与冠状动脉痉挛显著相关。这一发现表明冠状动脉痉挛中存在遗传因素。然而，应该引起重视的是，环境因素，如吸烟，也是冠状动脉痉挛的重要危险因素。 ...更多信息 我们正在研究eNOS基因变异体本身是否对eNOS的合成或活性产生影响，我们最近的体外研究通过荧光素酶报告基因分析发现，只有5 '侧翼区的T-786*C变异体降低了eNOS基因的启动子活性。此外，我们的体内分析表明，冠状动脉内注射乙酰胆碱或硝酸甘油引起的冠状动脉直径的变化是更大的变异型等位基因的患者比野生型等位基因。这些累积的证据表明，T-786*C变异体可以被认为是冠状动脉痉挛的功能突变。就在最近，我们报道了eNOS基因变异体与其他心血管疾病如心肌梗死和原发性高血压有关。因此，关于eNOS基因变异的一系列研究可能不仅会对冠状动脉痉挛的病理生理学产生新的认识，而且也会对其他疾病的病理生理学产生新的认识。常见的心血管疾病少

项目成果

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