Prostaglandin E2 protects the heart from ischemia-reperfusion injury via its receptor subtype EP4
Prostaglandin E2 protects the heart from ischemia-reperfusion injury via its receptor subtype EP4
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DOI：
10.1161/01.cir.0000128046.54681.97
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发表时间：
2004-05-25
期刊：
影响因子：
37.8
通讯作者：
Ushikubi, F
中科院分区：
文献类型：
--
作者：
Xiao, CY;Yuhki, K;Ushikubi, F
在急性心肌梗死的心脏中，前列腺素E-2的产生显著增加.此外，已报道PGE（2）受体（EP）的几种亚型在心脏中表达。然而，PGE（2）在心脏缺血再灌注（I/R）损伤中的作用仍不清楚。我们试图阐明PGE（2）通过EP 4（一种EP亚型）在I/R损伤中的作用，使用缺乏EP 4的小鼠（EP 4-/- mice）.方法和结果-在小鼠心室中，竞争性逆转录-聚合酶链反应揭示EP 4 mRNA在EP mRNA中的最高表达水平。在I/R模型中，EP 4-/-小鼠的梗死面积大于野生型小鼠;左前降支冠状动脉闭塞1小时，然后再灌注24小时。此外，根据Langendorff技术灌注的离体EP 4-/-心脏对I/R的反应比野生型心脏有更大的功能和生化紊乱。在体外实验中，EP 4激动剂AE 1 -329可显著提高非心肌细胞的cAMP浓度，而对心肌细胞的作用较弱。当在冠状动脉闭塞前1小时给予另一种EP 4激动剂4819-CD时，它显著减少了野生型小鼠的梗死面积。值得注意的是，即使在冠状动脉闭塞后50分钟给药，也观察到类似的心脏保护作用。结论-内源性PGE（2）和外源性EP 4激动剂通过EP 4保护心脏免受I/R损伤。4819-CD的强有力的心脏保护作用表明，该化合物将用于治疗急性心肌梗死。
Background - In the heart with acute myocardial infarction, production of prostaglandin (PG) E-2 increases significantly. In addition, several subtypes of PGE(2) receptors (EPs) have been reported to be expressed in the heart. The role of PGE(2) in cardiac ischemia-reperfusion (I/R) injury, however, remains unknown. We intended to clarify the role of PGE(2) via EP4, an EP subtype, in I/R injury using mice lacking EP4 (EP4-/- mice).Methods and Results - In murine cardiac ventricle, competitive reverse transcription - polymerase chain reaction revealed the highest expression level of EP4 mRNA among EP mRNAs. EP4-/- mice had larger infarct size than wild-type mice in a model of I/R; the left anterior descending coronary artery was occluded for 1 hour, followed by 24 hours of reperfusion. In addition, isolated EP4-/- hearts perfused according to the Langendorff technique had greater functional and biochemical derangements in response to I/R than wild-type hearts. In vitro, AE1-329, an EP4 agonist, raised cAMP concentration remarkably in noncardiomyocytes, whereas the action was weak in cardiomyocytes. When 4819-CD, another EP4 agonist, was administered 1 hour before coronary occlusion, it reduced infarct size significantly in wild-type mice. Notably, a similar cardioprotective effect was observed even when it was administered 50 minutes after coronary occlusion.Conclusions - Both endogenous PGE(2) and an exogenous EP4 agonist protect the heart from I/R injury via EP4. The potent cardioprotective effects of 4819-CD suggest that the compound would be useful for treatment of acute myocardial infarction.