Associations of the UCP2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women
Associations of the UCP2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women
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DOI：
10.1161/01.atv.0000153141.42033.22
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发表时间：
2005-03-01
影响因子：
8.7
通讯作者：
Patsch, W
中科院分区：
文献类型：
--
作者：
Oberkofler, H;Iglseder, B;Patsch, W
目的：活性氧(ROS)参与动脉粥样硬化的形成。在动物模型中，解偶联蛋白2(UCP2)减少线粒体ROS的产生，并对疾病具有保护作用。与肥胖和β细胞功能相关的常见-866G/A启动子多态性也可能影响UCP2基因在动脉壁细胞中的表达。方法和结果-UCP2基因3‘非翻译区-866G/A和45ntdel/INS多态在Salzburg动脉粥样硬化预防计划高危人群(SAPHIR)的1334名参与者中进行了基因分型。在女性研究参与者中，我们观察到-866G/A启动子多态和2-位点单倍型与无症状颈动脉粥样硬化之间的适度关联。功能研究显示-866G野生型等位基因在人脐静脉内皮细胞和分化的THP-1细胞中表达增加。对不同细胞系的核提取液进行的凝胶迁移率改变分析和抗体干扰分析表明，细胞类型的特异性蛋白复合体与围绕-866位点的区域结合，提示缺氧诱导因子1α参与了内皮细胞和巨噬细胞中UCP2基因表达的调节。结论-我们的结果提示UCP2在动脉粥样硬化形成中的作用，最初是从动物和细胞培养模型的研究中提出的。
Objective - Reactive oxygen species (ROS) contribute to atherogenesis. Uncoupling protein 2 (UCP2) reduces mitochondrial ROS generation and protects against the disease in animal models. A common -866G/A promoter polymorphism that has been associated with obesity and beta-cell function may also affect UCP2 gene expression in cells of the arterial wall.Methods and Results - Genotype distributions of the -866G/A and of a 45nt-del/ins polymorphism in the 3'-untranslated region of the UCP2 gene were determined in 1334 participants of the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR). We observed a modest association of the -866G/A promoter polymorphism and 2-loci haplotypes with asymptomatic carotid atherosclerosis in female study participants. Functional studies revealed increased expression of the -866G wild-type allele in human umbilical vein endothelial cells and differentiated THP-1 cells. Electrophoretic mobility shift assay studies and antibody-interference assays performed with nuclear extracts of various cell lines showed binding of cell-type specific protein complexes to the region encompassing the -866 site and suggested involvement of hypoxia inducible factor 1alpha in the regulation of UCP2 gene expression in endothelial cells and macrophages.Conclusions - Our results suggest a role of UCP2 in atherogenesis as originally proposed from studies in animal and cell culture models.