Cardiospecific overexpression of the prostaglandin EP3 receptor attenuates ischemia-induced myocardial injury
Cardiospecific overexpression of the prostaglandin EP3 receptor attenuates ischemia-induced myocardial injury
复制标题
DOI：
10.1161/circulationaha.104.508333
复制
发表时间：
2005-07-19
期刊：
影响因子：
37.8
通讯作者：
Hohlfeld, T
中科院分区：
文献类型：
--
作者：
Martin, M;Meyer-Kirchrath, J;Hohlfeld, T
背景--急性心肌缺血和再灌注时前列腺素E-2（PGE（2））的生成显著增加. PGE（2）与其它洋地黄素一样，对缺血再灌注心肌有保护作用。已经假设，这种心脏保护是由G（i）-偶联EP 3亚型的E-型前列腺素受体介导的。方法和结果-我们通过产生具有心脏特异性EP 3受体过表达的转基因（tg）小鼠来测试这一假设。根据配体结合，一个40倍的过度表达的EP 3受体，实现了从TG心脏相比，野生型（野生型）同窝仔制备的膜。在从tg小鼠分离的心肌细胞中，毛喉素诱导的cAMP升高显著减弱，表明过表达的EP 3受体与具有组成性受体活性的抑制性G蛋白（G（i））偶联。没有证据表明EP 3受体偶联G（q）介导的蛋白激酶C信号传导。将tg和wt小鼠的离体心脏进行60分钟的无血流缺血和45分钟的再灌注。与野生型心脏相比，tg心脏的缺血性挛缩明显延迟，缺血引起的左心室舒张末期压升高降低了55%。肌酸激酶和乳酸脱氢酶的释放显着下降了85%和73%，分别与WT hearts.Conclusions相比，组成型前列腺素EP 3受体信号传导对心肌细胞，这可能是Gi介导的，并导致在缺血和再灌注心肌损伤的显着衰减的保护作用。E-型野牡丹素的神经保护作用可能是由这种受体亚型介导的。
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.