Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function
Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function
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DOI：
10.1161/01.cir.0000091255.63645.98
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发表时间：
2003-09-23
期刊：
影响因子：
37.8
通讯作者：
Kugiyama, K
中科院分区：
文献类型：
--
作者：
Nakamura, S;Sugiyama, S;Kugiyama, K
背景-谷氨酸半胱氨酸连接酶(GCLM)修饰亚单位基因-588C/T多态的Minor-588T等位基因与血浆GSH水平降低相关，是心肌梗死的危险因素。方法和结果：我们在157名冠状动脉造影正常的连续受试者中检测了-588C/T多态对冠状动脉内径和冠状动脉内注射乙酰胆碱的血流反应的影响。在包括传统危险因素在内的协变量的多元线性回归分析中，Minor-588T等位基因与乙酰胆碱所致的心外膜冠状动脉扩张受损或收缩增强独立相关，与乙酰胆碱所致冠状动脉血流反应迟钝相关。在59名连续受试者中，冠状动脉内注射N-G-单甲基-L-精氨酸的收缩反应反映了冠状动脉一氧化氮(NO)生物活性的存在，与-588T等位基因在多因素分析中呈负相关且独立相关。结论GCLM基因-588T多态导致大、阻力冠状动脉内皮细胞NO生物活性降低，导致内皮依赖性血管舒缩功能受损。GCL-GSH-NO轴可能在冠心病防御系统中发挥作用。
Background - The minor -588T allele of polymorphism - 588C/T of a modifier subunit gene in glutamate-cysteine ligase (GCLM), a rate-limiting enzyme for glutathione (GSH) synthesis, was associated with lower plasma GSH levels and was a risk factor for myocardial infarction.Methods and Results - We examined effects of the - 588C/T polymorphism on coronary arterial diameter and blood flow responses to intracoronary infusion of acetylcholine in 157 consecutive subjects who had normal coronary angiograms. In multivariate linear regression analysis with covariates including traditional risk factors, the minor -588T allele had an independent association with impaired dilation or enhanced constriction of epicardial coronary arteries in response to acetylcholine, and it was independently associated with blunted increase in coronary flow response to acetylcholine. In a subgroup of 59 consecutive subjects, constrictor responses of epicardial coronary diameter to intracoronary infusion of N-G-monomethyl-L-arginine, reflecting the presence of coronary nitric oxide (NO) bioactivity, had an inverse and independent association with the -588T allele in multivariate analysis.Conclusions - The -588T polymorphism of the GCLM gene causes a decrease in endothelial NO bioactivity, leading to impairment of endothelium-dependent vasomotor function in large and resistance coronary arteries. The GCL-GSH-NO axis may play a role in the defense system against coronary artery disease.