Published online before print January 15, 2009, doi: 10.1161/ATVBAHA.108.183160
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© 2009 American Heart Association, Inc.
Cell Biology/Signaling |
Antiplatelet Actions of Statins and Fibrates Are Mediated by PPARs
From Cardiothoracic Pharmacology (F.Y.A., M.J.P.-C., J.A.M.), National Heart and Lung Institute, Imperial College, London, UK; The William Harvey Research Institute (F.Y.A., P.C.J.A., A.-R.A.D., A.T.T., T.D.W.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK; and The Ernest Cooke Vascular & Microvascular Unit (A.T.T.), St. Bartholomew’s Hospital, London, UK.
Correspondence to Timothy D. Warner, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. E-mail t.d.warner{at}qmul.ac.uk
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
and PPAR
. The effects of simvastatin were prevented by the PPAR antagonist GW9662 or the PPAR antagonist GW6471. In a small-scale human study fluvastatin activated PPAR and PPAR in platelets and reduced aggregation in response to arachidonic acid ex vivo. The effects of fenofibrate were prevented by PPAR antagonism with GW6471. Fenofibrate increased bleeding time in wild-type, but not in PPAR–/– mice. The inhibitory effect of fenofibrate, but not simvastatin, on aggregation was prevented by deletion of PPAR in murine platelets. PKC, which influences platelet activation, associated and immune-precipitated with PPAR in platelets stimulated with statins and with PPAR 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 in platelets also provide a mechanism by which these effects are mediated.
We show statins and fibrates inhibit platelet activation while activating PPAR and PPAR in vitro and in vivo. Addition of antagonists for these receptors tohuman platelets or deletion of PPAR in murine platelets resulted in a reduction of the inhibitory effects of these drugs.
Key Words: platelets • statin • fibrate • PPAR, PPAR
Related Article:
Arterioscler Thromb Vasc Biol 2009 29: 620-621.
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  R. P. Phipps and N. Blumberg Statin Islands and PPAR Ligands in Platelets Arterioscler Thromb Vasc Biol, May 1, 2009; 29(5): 620 - 621. [Full Text] [PDF]
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