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

Abstract

Background— In the heart with acute myocardial infarction, production of prostaglandin (PG) E₂ increases significantly. In addition, several subtypes of PGE₂ receptors (EPs) have been reported to be expressed in the heart. The role of PGE₂ in cardiac ischemia-reperfusion (I/R) injury, however, remains unknown. We intended to clarify the role of PGE₂ 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 PGE₂ 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.