Microsomal prostaglandin E synthase‐1 inhibition prevents adverse cardiac remodelling after myocardial infarction in mice

Abstract

Background and PurposeHeart failure with reduced ejection fraction (HFrEF) is a major consequence of myocardial infarction (MI). The microsomal prostaglandin E synthase‐1 (mPGES‐1)/PGE2 pathway has been shown to constrain reperfusion injury after acute myocardial ischaemia. However, it is unknown whether pharmacological inhibition of mPGES‐1, a target with lower risk of thrombosis compared with selective inhibition of cyclooxygenase‐2, affects chronic cardiac remodelling after MI.Experimental ApproachMice were subjected to left anterior descending coronary artery ligation, followed by intraperitoneal treatment with the mPGES‐1 inhibitor compound III (CIII) or 118, celecoxib (cyclooxygenase‐2 inhibitor) or vehicle, once daily for 28 days. Urinary prostanoid metabolites were measured by liquid chromatography–tandem mass spectrometry.Key ResultsChronic administration of CIII improved cardiac function in mice after MI compared with vehicle or celecoxib. CIII did not affect thrombogenesis or blood pressure. In addition, CIII reduced infarct area, augmented scar thickness, decreased collagen I/III ratio, decreased the expression of fibrosis‐related genes and increased capillary density in the ischaemic area. Shunting to urinary metabolites of PGI2, not thromboxane B2 or PGD2, after inhibition of mPGES‐1 was positively correlated with cardiac function after MI. CIII administration significantly increased urinary PGI2/PGE2 metabolite ratio compared to vehicle or celecoxib. The PGI2/PGE2 metabolite ratio correlated positively with ejection fraction, fractional shortening and scar thickness. Treatment with 118 also improved cardiac function.Conclusion and ImplicationsInhibition of mPGES‐1 prevented chronic adverse cardiac remodelling via an augmented PGI2/PGE2 metabolite ratio and therefore represents a potential therapeutic strategy for development of HFrEF after MI.