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