Antiplatelet actions of statins and fibrates are mediated by PPARs.
OBJECTIVE
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.


RESULTS
We used a range of approaches to show statins inhibit human platelet activation in vitro while engaging PPARalpha and PPARgamma. The effects of simvastatin were prevented by the PPARgamma antagonist GW9662 or the PPARalpha antagonist GW6471. In a small-scale human study fluvastatin activated PPARalpha and PPARgamma in platelets and reduced aggregation in response to arachidonic acid ex vivo. The effects of fenofibrate were prevented by PPARalpha antagonism with GW6471. Fenofibrate increased bleeding time in wild-type, but not in PPARalpha-/- mice. The inhibitory effect of fenofibrate, but not simvastatin, on aggregation was prevented by deletion of PPARalpha in murine platelets. PKCalpha, which influences platelet activation, associated and immune-precipitated with PPARgamma in platelets stimulated with statins and with PPARalpha 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 PKCalpha in platelets also provide a mechanism by which these effects are mediated.
Ali
Ferhana Y
FY
Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, London, UK.
Armstrong
Paul C J
PC
Dhanji
Al-Rehan A
AR
Tucker
Arthur T
AT
Paul-Clark
Mark J
MJ
Mitchell
Jane A
JA
Warner
Timothy D
TD
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002995:Clofibric Acid / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000187:drug effects; D047495:PPAR gamma / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D010975:Platelet Aggregation Inhibitors; D002995:Clofibric Acid