LAUSR

BACKGROUND Heart failure with reduced ejection fraction (HFrEF) is a major consequence of myocardial infarction (MI). We have previously demonstrated that the microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 pathway constrains reperfusion injury after acute myocardial ischemia. However, it is unknown whether pharmacological inhibition of mPGES-1, a target with lower risk of thrombosis compared with cyclooxygenase-2 selective non-steroid anti-inflammatory drugs (NSAIDs), affects chronic cardiac remodeling after MI. EXPERIMENTAL APPROACH Mice were subjected to left anterior descending coronary artery ligation, followed by intraperitoneal treatment with the mPGES-1 inhibitor 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 RESULTS Chronic administration of CIII improved cardiac function in mice after MI compared with the 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 ischemic area. Shunting to urinary metabolites of PGI2, not thromboxane B2 or PGD2 , after inhibition of mPGES-1 was positively correlated with cardiac function post-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 Inhibition of mPGES-1 prevented chronic adverse cardiac remodeling via an augmented PGI2 /PGE2 metabolite ratio and therefore represents a potential therapeutic strategy for development of HFrEF post-MI.