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

Abstract

Objectives— Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a nuclear receptor found in platelets. PPARβ/δ agonists acutely inhibit platelet function within a few minutes of addition. As platelets are anucleated, the effects of PPARβ/δ agonists on platelets must be nongenomic. Currently, the particular role of PPARβ/δ receptors and their intracellular signaling pathways in platelets are not known. Methods and Results— We have used mice lacking PPARβ/δ (PPARβ/δ −/− ) to show the effects of the PPARβ/δ agonist GW501516 on platelet adhesion and cAMP levels are mediated specifically by PPARβ/δ, however GW501516 had no PPARβ/δ-specific effect on platelet aggregation. Studies in human platelets showed that PKCα, which can mediate platelet activation, was bound and repressed by PPARβ/δ 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.