Cardiospecific Overexpression of the Prostaglandin EP 3 Receptor Attenuates Ischemia-Induced Myocardial Injury

Abstract

The generation of prostaglandin E2 (PGE2) is significantly increased in acute myocardial ischemia and reperfusion. PGE2, in addition to other prostaglandins, protects the reperfused ischemic myocardium. It has been hypothesized that this cardioprotection is mediated by E-type prostaglandin receptors of the Gi-coupled EP3 subtype. We tested this hypothesis by generating transgenic (tg) mice with cardiospecific overexpression of the EP3 receptor. According to ligand binding, a 40-fold overexpression of the EP3 receptor was achieved in membranes prepared from tg hearts compared with wild-type (wt) littermates. In isolated cardiomyocytes from tg mice, the forskolin-induced rise in cAMP was markedly attenuated, indicating coupling of the overexpressed EP3 receptor to inhibitory G proteins (Gi) with constitutive receptor activity. There was no evidence for EP3 receptor coupling to Gq-mediated protein kinase C signaling. Isolated hearts from tg and wt mice were subjected to 60 minutes of no-flow ischemia and 45 minutes of reperfusion. In tg hearts, ischemic contracture was markedly delayed compared with wt hearts, and the ischemia-induced increase in left ventricular end-diastolic pressure was reduced by 55%. Creatine kinase and lactate dehydrogenase release was significantly decreased by 85% and 73%, respectively, compared with wt hearts. Constitutive prostaglandin EP3 receptor signaling exerts a protective effect on cardiomyocytes, which is probably Gi mediated and results in a remarkable attenuation of myocardial injury during ischemia and reperfusion. Cardioprotective actions of E-type prostaglandins may be mediated by this receptor subtype.