Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation

作     者：Blair, A Shaul, PW Yuhanna, IS Conrad, PA Smart, EJ 

作者机构：Univ Kentucky Dept Physiol Sch Med Lexington KY 40536 USA Univ Texas SW Med Ctr Dept Pediat Dallas TX 75235 USA Bucknell Univ Dept Biol Lewisburg PA 17837 USA 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：1999年第274卷第45期

页      面：32512-32519页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：NHLBI NIH HHS [HL58475  HL62844  HL58888] Funding Source: Medline 

主　　题：细胞膜/药物作用 细胞膜/酶学 细胞 培养的 胆固醇/代谢 环糊精类/药理学 内皮 血管/药物作用 内皮 血管/酶学 酶激活 荧光抗体技术 间接 脂蛋白类 HDL/代谢 脂蛋白类 LDL/代谢 肉豆蔻酸/代谢 一氧化氮合酶/代谢 一氧化氮合酶Ⅲ型 棕榈酸/代谢 磷酰化 猪 动物 

摘      要：Hypercholesterolemia-induced vascular disease and atherosclerosis are characterized by a decrease in the bioavailability of endothelium-derived nitric oxide. Endothelial nitric-oxide synthase (eNOS) associates with caveolae and is directly regulated by the caveola protein, caveolin. In the present study, we examined the effects of oxidized low density Lipoprotein (oxLDL) on the subcellular location of eNOS, on eNOS activation, and on caveola cholesterol in endothelial cells. We found that treatment with 10 mu g/ml oxLDL for 60 min caused greater than 90% of eNOS and caveolin to leave caveolae, Treatment with oxLDL also inhibited acetylcholine-indnced activation of eNOS but not prostacyclin production. oxLDL did nob affect total cellular eNOS abundance. Oxidized LDL also did not affect the palmitoylation, myristoylation or phosphorylation of eNOS. Oxidized LDL, but not native LDL, or HDL depleted caveolae of cholesterol by serving as an acceptor for cholesterol. Cyclodextrin also depleted caveolae of cholesterol and caused eNOS and caveolin to translocate from caveolae. Furthermore, removal of oxLDL allowed eNOS and caveolin to return to caveolae. We conclude that oxLDL-induced depletion of caveola cholesterol causes eNOS to leave caveolae and inhibits acetylcholine-induced activation of the enzyme. This process may be an important mechanism in the early pathogenesis of atherosclerosis.