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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1871.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

PPARβ/ Agonists Modulate Platelet Function via a Mechanism Involving PPAR Receptors and Specific Association/Repression of PKC–Brief Report

Ferhana Y. Ali; Matthew G. Hall; Béatrice Desvergne; Timothy D. Warner; Jane A. Mitchell

From Cardiothoracic Pharmacology (F.Y.A., J.A.M.), National Heart and Lung Institute, Imperial College London, UK; Queen Mary University of London (F.Y.A., T.D.W.), Barts and the London School of Medicine and Dentistry, The William Harvey Research Institute, UK and the Center for Integrative Genomics (M.G.H., B.D.), University of Lausanne, Switzerland.

Correspondence to Jane A. Mitchell, Cardiothoracic Pharmacology, NHLI, Imperial College London, Dovehouse Street, London SW3 6LY, UK. E-mail j.a.mitchell{at}imperial.ac.uk

Objectives— Peroxisome proliferator-activated receptor β/ (PPARβ/) is a nuclear receptor found in platelets. PPARβ/ agonists acutely inhibit platelet function within a few minutes of addition. As platelets are anucleated, the effects of PPARβ/ agonists on platelets must be nongenomic. Currently, the particular role of PPARβ/ receptors and their intracellular signaling pathways in platelets are not known.

Methods and Results— We have used mice lacking PPARβ/ (PPARβ/^–/–) to show the effects of the PPARβ/ agonist GW501516 on platelet adhesion and cAMP levels are mediated specifically by PPARβ/, however GW501516 had no PPARβ/-specific effect on platelet aggregation. Studies in human platelets showed that PKC, which can mediate platelet activation, was bound and repressed by PPARβ/ after platelets were treated with GW501516.

Conclusions— These data provide evidence of a novel mechanism by which PPAR receptors influence platelet activity and thereby thrombotic risk.

We show activation of platelet PPARβ/ results in binding to and repression of PKC, thus providing a signaling pathway for PPARβ/ in platelets. Deletion of PPARβ/ in murine platelets resulted in a loss of the inhibitory effects on adhesion and cAMP release, indicating PPARβ/ is involved in platelet activation pathways.

Key Words: platelets • PPARβ/ • PKC • knockout mice