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

在冠脉痉挛的病理生理研究中，我们最近报道冠脉痉挛患者的冠状动脉中存在一氧化氮(NO)活性不足。这一结论是在心导管插管期间冠状动脉内注射一氧化氮合酶(NOS)抑制剂LNMMA得到的。冠状动脉痉挛在日本人中比在高加索人中普遍，提示遗传因素参与了其发病机制。通过对内皮型一氧化氮合酶(ENOS)基因的遗传分析，发现冠脉痉挛患者eNOS基因编码区存在Glu298Asp错义突变，eNOS基因5‘侧翼区存在T-786*CA-922*G和T-1468*A三个连锁突变。这些变异与冠状动脉痉挛密切相关。这一发现表明冠状动脉痉挛存在遗传因素。然而，应该理解的是，吸烟等环境因素也是冠状动脉痉挛的重要危险因素。…我们最近的体外研究表明，通过荧光素酶报告基因分析，只有5‘-侧翼区的T-786*C变体降低了eNOS基因的启动子活性。此外，我们的体内分析显示，冠状动脉内注射乙酰胆碱或硝酸甘油引起的冠状动脉内径变化在变异类型等位基因患者中比那些携带野生型等位基因的患者更大。这些证据表明，T-786*C变异可以被认为是冠状动脉痉挛的一种功能突变。最近，我们报道了eNOS基因变异与其他心血管疾病，如心肌梗死和高血压相关，因此，对eNOS基因变异的一系列研究可能会对冠状动脉痉挛以及其他常见心血管疾病的病理生理有新的认识。较少

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