Abstract 522: Specific Oxidized Phospholipids Modulate Platelet Reactivity In Vivo During Hyperlipidemia Via Cd36: A Mechanism Linking Hyperlipidemia, Oxidant Stress And A Pro-thrombotic Phenotype
Enhanced platelet reactivity is critical to the pathophysiology of occlusive arterial thrombotic disease. Despite the strong clinical associations between hyperlipidemia, a major risk factor for atherosclerosis, and a pro-thrombotic phenotype, the mechanisms responsible for enhanced platelet reactivity during hyperlipidemia remain unknown. Pro-atherosclerotic lipid abnormalities such as hypercholesterolemia are associated with both enhanced oxidant stress and generation of biologically active oxidized lipids, including potential ligands for the scavenger receptor CD36, a major platelet surface glycoprotein. Using multiple murine in vivo thrombosis models we now demonstrate that hyperlipidemic atherosclerosis prone mice (apolipoprotein E-deficient or LDL receptor-deficient) form occlusive intravascular thrombi faster than wildtype mice, and that genetic deletion of CD36 protects mice from hyperlipidemia-associated enhanced platelet reactivity and accompanying pro-thrombotic phenotype. Structurally defined oxidized choline glycerophospholipid molecular species that serve as endogenous high affinity ligands for CD36 are shown to :
be markedly increased in plasma of hyperlipidemic mice;
be elevated in plasma of subjects with low HDL levels; and
to promote platelet activation and alpha-granule release via CD36 at pathophysiological levels.
These studies thus demonstrate that platelet CD36 interactions with specific endogenous oxidized lipids play a heretofore unrecognized role in the well-known clinical associations between hyperlipidemia, oxidant stress and a prothrombotic phenotype.