Cholesterol-Lowering Drugs Inhibit Lectin-Like Oxidized Low-Density Lipoprotein-1 Receptor Function by Membrane Raft Disruption
Cholesterol-Lowering Drugs Inhibit Lectin-Like Oxidized Low-Density Lipoprotein-1 Receptor Function by Membrane Raft Disruption
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DOI：
10.1124/mol.112.078915
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发表时间：
2012-08-01
影响因子：
3.6
通讯作者：
Biocca, Silvia
中科院分区：
文献类型：
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作者：
Matarazzo, Sara;Quitadamo, Maria Chiara;Biocca, Silvia
凝集素样氧化低密度脂蛋白（LOX-1）是内皮细胞氧化低密度脂蛋白（ox-LDL）的主要受体，在动脉粥样硬化病变中上调。他汀类药物是心血管疾病的主要治疗药物，已知可下调LOX-1的表达。对LOX-1受体的影响是否与他汀类药物介导的降胆固醇活性有关尚不清楚。我们研究了LOX-1介导的脂质颗粒内化、运输和加工对胆固醇的需求，以及他汀类药物作为LOX-1功能抑制剂的作用。通过将细胞急性暴露于甲基-β-环糊精或慢性暴露于不同的他汀类药物（洛伐他汀和阿托伐他汀）来破坏富含胆固醇的膜微区，导致质膜中LOX-1的空间结构紊乱，并且在ox-LDL结合和内化方面特异性LOX-1功能显著丧失。亚细胞分级分离和免疫化学研究表明LOX-1天然存在于富含小窝的脂筏中，并且通过胆固醇减少，该级分中LOX-1的量高度降低（>= 60%）。相反，异戊二烯化抑制对LOX-1受体的分布和功能没有影响。此外，在动脉粥样硬化的人主动脉病变的原代培养物中，我们证实了LOX-1存在于富含小窝的脂筏中，并证明洛伐他汀治疗导致LOX-1在脂筏中的下调和ox-LDL诱导的凋亡表型的拯救。总之，我们的数据揭示了以前未被认识到的膜胆固醇对LOX-1受体活性的重要作用，并表明他汀类药物通过破坏膜筏和损害LOX-1受体功能来保护血管内皮免受ox-LDL的不良影响。
Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells, is up-regulated in atherosclerotic lesions. Statins are the principal therapeutic agents for cardiovascular diseases and are known to down-regulate LOX-1 expression. Whether the effect on the LOX-1 receptor is related to statin-mediated cholesterol-lowering activity is unknown. We investigate the requirement of cholesterol for LOX-1-mediated lipid particle internalization, trafficking, and processing and the role of statins as inhibitors of LOX-1 function. Disruption of cholesterol-rich membrane microdomains by acute exposure of cells to methyl-beta-cyclodextrin or chronic exposure to different statins (lovastatin and atorvastatin) led to a spatial disorganization of LOX-1 in plasma membranes and a marked loss of specific LOX-1 function in terms of ox-LDL binding and internalization. Subcellular fractionation and immunochemical studies indicate that LOX-1 is naturally present in caveolae-enriched lipid rafts and, by cholesterol reduction, the amount of LOX-1 in this fraction is highly decreased(>= 60%). In contrast, isoprenylation inhibition had no effect on the distribution and function of LOX-1 receptors. Furthermore, in primary cultures from atherosclerotic human aorta lesions, we confirm the presence of LOX-1 in caveolae-enriched lipid rafts and demonstrate that lovastatin treatment led to down-regulation of LOX-1 in lipid rafts and rescue of the ox-LDL-induced apoptotic phenotype. Taken together, our data reveal a previously unrecognized essential role of membrane cholesterol for LOX-1 receptor activity and suggest that statins protect vascular endothelium against the adverse effect of ox-LDL by disruption of membrane rafts and impairment of LOX-1 receptor function.