Prostaglandin E2 protects the heart from ischemia-reperfusion injury via its receptor subtype EP4

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.