title: Cholesterol-lowering drugs inhibit lectin-like oxidized low-density lipoprotein-1 receptor function by membrane raft disruption.
abstract: 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.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Matarazzo
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Quitadamo
authors.forename: Ruggiero
authors.initials: R
authors.lastname: Mango
authors.forename: Sarah
authors.initials: S
authors.lastname: Ciccone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Biocca
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000172:deficiency / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D000924:Anticholesteremic Agents; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D002784:Cholesterol