Cholesterol-lowering drugs inhibit LOX-1 receptor function by membrane raft disruption

Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for ox-LDL in endothelial cells, is up-regulated in atherosclerosis lesions. Statins are principal therapeutic agents for cardiovascular diseases and are known to down regulate LOX-1 expression. Whether the effect on LOX-1 receptor is related to statin-mediated cholesterol lowering activity is unknown. We seek to 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 (MβCD) 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 caveolaeenriched lipid rafts and demonstrate that lovastatin treatment led to down-regulation of LOX-1 in lipid rafts and rescue of 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.