Cardiospecific Overexpression of the Prostaglandin EP 3 Receptor Attenuates Ischemia-Induced Myocardial Injury
- 19 July 2005
- journal article
- research article
- Published by Wolters Kluwer Health in Circulation
- Vol. 112 (3), 400-406
- https://doi.org/10.1161/circulationaha.104.508333
Abstract
Background— The generation of prostaglandin E 2 (PGE 2 ) is significantly increased in acute myocardial ischemia and reperfusion. PGE 2 , 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 EP 3 subtype. Methods and Results— We tested this hypothesis by generating transgenic (tg) mice with cardiospecific overexpression of the EP 3 receptor. According to ligand binding, a 40-fold overexpression of the EP 3 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 EP 3 receptor to inhibitory G proteins (G i ) with constitutive receptor activity. There was no evidence for EP 3 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 EP 3 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.Keywords
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