Martin Melanie, Meyer-Kirchrath Jutta, Kaber Gernot, Jacoby Christoph, Flögel Ulrich, Schrader Jürgen, Rüther Ulrich, Schrör Karsten, Hohlfeld Thomas
Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Moorenstr 5, D-40225 Düsseldorf, Germany.
Circulation. 2005 Jul 19;112(3):400-6. doi: 10.1161/CIRCULATIONAHA.104.508333. Epub 2005 Jul 11.
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.
急性心肌缺血和再灌注时前列腺素E2（PGE2）的生成显著增加。PGE2与其他前列腺素一起可保护再灌注的缺血心肌。据推测，这种心脏保护作用是由Gi偶联的EP3亚型E型前列腺素受体介导的。
我们通过构建心脏特异性过表达EP3受体的转基因（tg）小鼠来验证这一假设。根据配体结合情况，与野生型（wt）同窝小鼠相比，tg心脏制备的膜中EP3受体过表达了40倍。在tg小鼠分离的心肌细胞中，福斯可林诱导的cAMP升高明显减弱，表明过表达的EP3受体与具有组成型受体活性的抑制性G蛋白（Gi）偶联。没有证据表明EP3受体与Gq介导的蛋白激酶C信号传导偶联。将tg和wt小鼠的离体心脏进行60分钟无血流缺血和45分钟再灌注。与wt心脏相比，tg心脏的缺血性挛缩明显延迟，缺血诱导的左心室舒张末期压力升高降低了55%。与wt心脏相比，肌酸激酶和乳酸脱氢酶的释放分别显著降低了85%和73%。
组成型前列腺素EP3受体信号传导对心肌细胞具有保护作用，这可能是由Gi介导的，可显著减轻缺血和再灌注期间的心肌损伤。E型前列腺素的心脏保护作用可能由该受体亚型介导。
