Critical role of peroxisome proliferator-activated receptor a in promoting platelet hyperreactivity and thrombosis under hyperlipidemia

Platelet hyperreactivity and increased atherothrombotic risk are specifically associated with dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPAR alpha) is an important regulator of lipid metabolism. It has been suggested to affect both thrombosis and hemostasis, yet the underlying mechanisms are not well understood. In this study, the role and mechanism of PPAR alpha in platelet activation and thrombosis related to dyslipidemia were examined. Employing mice with deletion of PPAR alpha (Ppar alpha(-/-)), we demonstrated that PPAR alpha is required for platelet activation and thrombus formation. The effect of PPARa is critically dependent on platelet dense granule secretion, and is contributed by p38MAPK/Akt, fatty acid b-oxidation, and NAD(P)H oxidase pathways. Importantly, PPAR alpha and the associated pathways mediated a prothrombotic state induced by a high-fat diet and platelet hyperactivity provoked by oxidized low density lipoproteins. Platelet reactivity was positively correlated with the levels of expression of PPAR alpha, as revealed by data from wild-type, chimeric (Ppar alpha(+/-)), and Ppara(-/-) mice. This positive correlation was recapitulated in platelets from hyperlipidemic patients. In a lipid-treated megakaryocytic cell line, the lipid-induced reactive oxygen species-NF-kB pathway was revealed to upregulate platelet PPAR alpha in hyperlipidemia. These data suggest that platelet PPAR alpha critically mediates platelet activation and contributes to the prothrombotic status under hyperlipidemia.