Antiplatelet Actions of Statins and Fibrates Are Mediated by PPARs

Objectives-Statins and fibrates are hypolipidemic drugs which decrease cardiac events in individuals without raised levels of cholesterol. These drugs inhibit platelet function, but the mechanisms by which this pleiotropic effect is exerted are not known. Methods and Results-We used a range of approaches to show statins inhibit human platelet activation in vitro while engaging PPAR alpha and PPAR gamma. The effects of simvastatin were prevented by the PPAR gamma antagonist GW9662 or the PPAR alpha antagonist GW6471. In a small-scale human study fluvastatin activated PPAR alpha and PPAR gamma in platelets and reduced aggregation in response to arachidonic acid ex vivo. The effects of fenofibrate were prevented by PPAR alpha antagonism with GW6471. Fenofibrate increased bleeding time in wild-type, but not in PPAR alpha(-/-) mice. The inhibitory effect of fenofibrate, but not simvastatin, on aggregation was prevented by deletion of PPAR alpha in murine platelets. PKC alpha, which influences platelet activation, associated and immune-precipitated with PPAR gamma in platelets stimulated with statins and with PPAR alpha in platelets stimulated with fenofibrate. Conclusions-This study is the first to provide a unifying explanation of how fibrates and statins reduce thrombotic and cardiovascular risk. Our findings that PPARs associate with PKC alpha in platelets also provide a mechanism by which these effects are mediated. (Arterioscler Thromb Vasc Biol. 2009; 29: 706-711.)