Cardiospecific overexpression of the prostaglandin EP3 receptor attenuates ischemia-induced myocardial injury

Article

关键词: INFARCT SIZE;    SELECTIVE ACTIVATION;    MULTIPLE ISOFORMS;    EXPRESSION;    HEARTS;    ATP;    MECHANISMS;    EP3-RECEPTOR;    CONTRACTURE;    PROTECTION;   

DOI  :  10.1161/CIRCULATIONAHA.104.508333

来源: SCIE

【 摘 要 】

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 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 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.

【 授权许可】

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