Department of Clinical Chemistry, University Medicine Göttingen, Germany.
Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1890-3. doi: 10.1161/ATVBAHA.109.190678. Epub 2009 Aug 20.
Homozygosity for the -786C-variant of the human nos-3 gene is a risk factor for coronary artery disease (CAD). Interestingly, affected individuals develop CAD more frequently but not earlier than the general population.
Genotyped primary human umbilical vein endothelial cells (ECs) were exposed to fluid shear stress (FSS) and analyzed for nitric oxide (NO) and superoxide anion (O(2)(-)) formation as well as mRNA and protein expression of different antioxidant enzymes. Dysfunctional CC-genotype ECs failed to upregulate NO synthase expression in response to FSS and exhibited a reduced NO synthesis capacity when compared to functionally intact TT-genotype ECs. However, only CC-genotype ECs responded to FSS with an Egr-1-mediated increase in manganese-containing superoxide dismutase (SOD-2) expression, shielding them from endothelin-1-induced oxidative stress in a NO-independent manner.
This FSS-induced rise in SOD-2 expression in CC-genotype ECs effectively stabilizes their antiatherosclerotic phenotype and may explain not only the comparatively slow onset of CAD in homozygous carriers of the C-allele of the nos-3 gene but also define a general strategy for preventing endothelial dysfunction at the outset of atherosclerosis.
人类 nos-3 基因的-786C 变异纯合子是冠心病（CAD）的一个危险因素。有趣的是，受影响的个体比一般人群更频繁地但不是更早地发展为 CAD。
对经基因分型的原代人脐静脉内皮细胞（EC）进行流体剪切力（FSS）暴露，并分析一氧化氮（NO）和超氧阴离子（O（2）（-））的形成以及不同抗氧化酶的 mRNA 和蛋白表达。功能失调的 CC 基因型 EC 未能响应 FSS 而上调一氧化氮合酶表达，与功能完整的 TT 基因型 EC 相比，NO 合成能力降低。然而，只有 CC 基因型 EC 对 FSS 作出反应，通过 Egr-1 介导的锰结合超氧化物歧化酶（SOD-2）表达增加，以非 NO 依赖的方式保护它们免受内皮素-1 诱导的氧化应激。
这种 FSS 诱导的 CC 基因型 EC 中 SOD-2 表达的增加有效地稳定了它们的抗动脉粥样硬化表型，这不仅可以解释 nos-3 基因 C 等位基因纯合子携带者 CAD 发病相对较晚，而且还可以确定预防动脉粥样硬化起始时内皮功能障碍的一般策略。
