PGE2 decreases reactivity of human platelets by activating EP2 and EP4

Introduction: Platelet hyperreactivity associates with cardiovascular events in humans. Studies in mice and humans suggest that prostaglandin E(2) (PGE(2)) regulates platelet activation. In mice, activation of the PGE(2) receptor subtype 3 (EP3) promotes thrombosis, but the significance of EP3 in humans is less well understood. Objectives: To characterize the regulation of thromboxane-dependent human platelet activation by PGE(2). Patients/Methods: Platelets collected from nineteen healthy adults were studied using an agonist of the thromboxane receptor (U46,619), PGE(2), and selective agonists and/or antagonists of the EP receptor subtypes. Platelet activation was assayed by (1) optical aggregometry, (2) measurement of dense granule release, and (3) single-platelet counting. Results: Healthy volunteers demonstrated significant interindividual variation in platelet response to PGE(2). PGE(2) completely inhibited U46,619-induced platelet aggregation and ATP release in 26% of subjects; the remaining 74% had partial or no response to PGE(2). Antagonism of EP4 abolished the inhibitory effect of PGE(2). In all volunteers, a selective EP2 agonist inhibited U46,619-induced aggregation. Furthermore, the selective EP3 antagonist DG-041 converted all PGE(2) nonresponders to full responders. Conclusions: There is significant interindividual variation of platelet response to PGE(2) in humans. The balance between EP2, EP3, and EP4 activation determines its net effect. PGE(2) can prevent thromboxane-induced platelet aggregation in an EP4-dependent manner. EP3 antagonism converts platelets of nonresponders to a PGE(2)-responsive phenotype. These data suggest that therapeutic targeting of EP pathways may have cardiovascular benefit by decreasing platelet reactivity. (C) 2010 Elsevier Ltd. All rights reserved.