Oxidized high‐density lipoprotein inhibits platelet activation and aggregation via scavenger receptor BI

Oxidatively modified LDL (OxLDL) and HDL (OxHDL) are present in the intima of atheromatous plaques and in plasma. While prothrombotic activity of OxLDL mediated by platelet CD36 is established, the role of oxHDL in thrombosis is not known. We now report that OxHDL, but not native HDL, is a potent inhibitor of platelet activation and aggregation induced by physiological agonists. OxHDL inhibited key platelet activation events including the activation of integrin alpha IIb beta 3, alpha‐granule secretion and dense‐granule release. Oxidized lipoproteins are ligands for scavenger receptors CD36 and SR‐BI, both of which are expressed on platelets. Studies using CD36−/− or SR‐BI−/− platelets and blocking antibodies demonstrated that the anti‐thrombotic activity of OxHDL is mediated exclusively by platelet SR‐BI. Isolated SR‐BI−/− platelets were more responsive to agonists than WT platelets supporting a physiological role for platelet SR‐BI. Platelets from eNOS−/−, Akt‐1−/− and Akt‐2−/− mice were as sensitive to oxHDL as WT platelets, indicating that the OxHDL effect is mediated by a pathway different from the eNOS/Akt pathway. These novel findings demonstrate that HDL, upon oxidation, acquires an anti‐thrombotic activity mediated by platelet SR‐BI and suggest that oxHDL may counterbalance pro‐thrombotic activity of oxLDL. Support was by NIH grants HL077213 (EAP), HL071625 (TVB), and HL70083 (MF).