PT - JOURNAL ARTICLE AU - Sara Matarazzo AU - Maria Chiara Quitadamo AU - Ruggiero Mango AU - Sarah Ciccone AU - Giuseppe Novelli AU - Silvia Biocca TI - Cholesterol-Lowering Drugs Inhibit Lectin-Like Oxidized Low-Density Lipoprotein-1 Receptor Function by Membrane Raft Disruption AID - 10.1124/mol.112.078915 DP - 2012 Aug 01 TA - Molecular Pharmacology PG - 246--254 VI - 82 IP - 2 4099 - http://molpharm.aspetjournals.org/content/82/2/246.short 4100 - http://molpharm.aspetjournals.org/content/82/2/246.full SO - Mol Pharmacol2012 Aug 01; 82 AB - 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-β-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.