Antiplatelet actions of statins and fibrates are mediated by PPARs

Abstract

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 PPARα and PPARγ. The effects of simvastatin were prevented by the PPARγ antagonist GW9662 or the PPARα antagonist GW6471. In a small-scale human study fluvastatin activated PPARα and PPARγ in platelets and reduced aggregation in response to arachidonic acid ex vivo. The effects of fenofibrate were prevented by PPARα antagonism with GW6471. Fenofibrate increased bleeding time in wild-type, but not in PPARα mice. The inhibitory effect of fenofibrate, but not simvastatin, on aggregation was prevented by deletion of PPARα in murine platelets. PKCα, which influences platelet activation, associated and immune-precipitated with PPARγ in platelets stimulated with statins and with PPARα 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 PKCα in platelets also provide a mechanism by which these effects are mediated. © 2009 American Heart Association, Inc.