title: Oxidized high-density lipoprotein inhibits platelet activation and aggregation via scavenger receptor BI.
abstract: Numerous studies have reported the presence of oxidatively modified high-density lipoprotein (OxHDL) within the intima of atheromatous plaques as well as in plasma; however, its role in the pathogenesis of thrombotic disease is not established. We now report that OxHDL, but not native HDL, is a potent inhibitor of platelet activation and aggregation induced by physiologic agonists. This antithrombotic effect was concentration and time dependent and positively correlated with the degree of lipoprotein oxidation. Oxidized lipoproteins are known ligands for scavenger receptors type B, CD36 and scavenger receptor B type I (SR-BI), both of which are expressed on platelets. Studies using murine CD36(-/-) or SR-BI(-/-) platelets demonstrated that the antithrombotic activity of OxHDL depends on platelet SR-BI but not CD36. Binding to SR-BI was required since preincubation of human and murine platelets with anti-SR-BI blocking antibody abrogated the inhibitory effect of OxHDL. Agonist-induced aggregation of platelets from endothelial nitric oxide synthase (eNOS)(-/-), Akt-1(-/-), and Akt-2(-/-) mice was inhibited by OxHDL to the same degree as platelets from wild-type (WT) mice, indicating that the OxHDL effect is mediated by a pathway different from the eNOS/Akt pathway. These novel findings suggest that contrary to the prothrombotic activity of oxidized low-density lipoprotein (OxLDL), HDL upon oxidation acquires antithrombotic activity that depends on platelet SR-BI.
authors.affiliation: Departments of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Manojkumar
authors.initials: M
authors.lastname: Valiyaveettil
authors.forename: Niladri
authors.initials: N
authors.lastname: Kar
authors.forename: Mohammad Z
authors.initials: MZ
authors.lastname: Ashraf
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Byzova
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Podrez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051122:Scavenger Receptors, Class B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018955:CD36 Antigens; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D010975:Platelet Aggregation Inhibitors; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C099252:oxidized low density lipoprotein; D000255:Adenosine Triphosphate