Background--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 G_i-coupled EP₃ subtype.

Methods and Results--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 (G_i) with constitutive receptor activity. There was no evidence for EP₃ receptor coupling to G_q-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.

Conclusions--Constitutive prostaglandin EP₃ receptor signaling exerts a protective effect on cardiomyocytes, which is probably G_i 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.