Prostaglandin E 2 Protects the Heart From Ischemia-Reperfusion Injury via Its Receptor Subtype EP 4

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Abstract
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 EP 4 , an EP subtype, in I/R injury using mice lacking EP 4 (EP 4 −/− mice). Methods and Results— In murine cardiac ventricle, competitive reverse transcription–polymerase chain reaction revealed the highest expression level of EP 4 mRNA among EP mRNAs. EP 4 −/− 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 EP 4 −/− 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 EP 4 agonist, raised cAMP concentration remarkably in noncardiomyocytes, whereas the action was weak in cardiomyocytes. When 4819-CD, another EP 4 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 EP 4 agonist protect the heart from I/R injury via EP 4 . The potent cardioprotective effects of 4819-CD suggest that the compound would be useful for treatment of acute myocardial infarction.

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