权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of polymorphisms of γ-glutamylcysteine synthetase genes in pathogenesis of coronary spastic angina

γ-谷氨酰半胱氨酸合成酶基因多态性在冠状动脉痉挛性心绞痛发病机制中的作用

基本信息

批准号：
13670728
负责人：
KUGIYAMA Kiyotaka
金额：
$ 2.3万
依托单位：
University of Yamanashi (Faculty 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：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670728/
关键词：
glutathione coronary spastic angina oxidative stress myocardial Infarction endothelial function polymorphism

项目摘要

Human glutamate-cysteine ligase (GCL) is a rate-limiting enzyme for synthesis of glutathione (GSH) that plays a crucial role in antioxidant defense mechanisms in most mammalian cells, including vascular cells. GCL is a heterodimer composed of a heavy catalytic subunit (GCLC) and a light modifier subunit (GCLM). Oxidants transcriptionally upregulate GCL genes for GSH synthesis, providing a protective mechanism against oxidative stress-induced cellular dysfunction. We found a polymorphism (-588C/T) of GCLM gene and a polymorphism (-129C/T) of GCLC gene in which minor alleles showed lower promoter activity in response to oxidants in the luciferase reporter gene assay. The induction of GCLM mRNA expression in the cultured human monocytes-macrophages was less in the cells from subjects with the minor allele as compared with those without minor allele. Plasma GSH levels were significantly lower in subjects with the minor allele of GCLM polymorphism than those without the minor allele (2.1±0.3 versus 3.3±0.2 μmol/L; P=0.001). The frequency of each of the minor alleles was significantly higher in those with previous myocardial infarction than in the control. In multiple logistic regression analysis, each of the minor alleles of GCLC and GCLM genes was a risk factor for myocardial infarction independently of traditional coronary risk factors. Endothelium-dependent dilation of coronary arteries was impaired in the subjects with the minor allele of GCLC gene polymorphism as compared with the age-matched those without the minor allele. In conclusion the polymorphisms of GCLC and GCLM genes may suppress GCL genes induction response to an oxidant and it is implicated in coronary endothelial vasomotor dysfunction and myocardial infarction.

人谷氨酸-半胱氨酸连接酶（GCL）是谷胱甘肽（GSH）合成的限速酶，在大多数哺乳动物细胞（包括血管细胞）的抗氧化防御机制中起着至关重要的作用。GCL是由重催化亚基（GCLC）和轻修饰亚基（GCLM）组成的异二聚体。氧化剂转录上调GSH合成的GCL基因，为氧化应激诱导的细胞功能障碍提供保护机制。在荧光素酶报告基因检测中，我们发现GCLM基因的一个多态性（-588C/T）和GCLC基因的一个多态性（-129C/T），其中小的等位基因对氧化剂的反应表现出较低的启动子活性。在培养的人单核-巨噬细胞中，GCLM mRNA表达的诱导作用在来自具有次要等位基因的受试者的细胞中比在不具有次要等位基因的受试者的细胞中更小。携带GCLM基因次要等位基因的受试者血浆GSH水平显著低于不携带该等位基因的受试者（2.1±0.3 vs 3.3±0.2 μmol/L; P=0.001）。有心肌梗死史的患者中每个次要等位基因的频率均显著高于对照组。多元Logistic回归分析显示，GCLC和GCLM基因的每个次要等位基因都是心肌梗死的危险因素，独立于传统的冠状动脉危险因素。与年龄匹配的无GCLC基因多态性的受试者相比，GCLC基因多态性的次要等位基因的受试者的冠状动脉内皮依赖性扩张受损。结论GCLC和GCLM基因多态性可能抑制GCL基因对氧化剂的诱导反应，并与冠状动脉内皮功能障碍和心肌梗死有关。