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

Abstract

Background and Purpose Heart 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 Approach Mice 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 Results Chronic 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 Implications Inhibition 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.

Prostanoids in Cardiac and Vascular Remodeling

“…In contrast, mPGES-1 deletion in myeloid cells improves the post-MI survival rate without affecting cardiac function, fibrosis, hypertrophy, and infarct size. 138 mPGES-1 inhibition, but not celecoxib, improves cardiac fibrosis and reduces infarct size after MI, 139 due to the shunting of PGH 2 to the cardioprotective PGI 2 . 139,140 The effect of PGE 2 in adult myocardium is mediated mainly by EPr2, EPr3, or EPr4.…”

“…138 mPGES-1 inhibition, but not celecoxib, improves cardiac fibrosis and reduces infarct size after MI, 139 due to the shunting of PGH 2 to the cardioprotective PGI 2 . 139,140 The effect of PGE 2 in adult myocardium is mediated mainly by EPr2, EPr3, or EPr4. 3 EPr2 deletion exacerbates myocardial injury after MI by reducing inflammatory macrophages in the infarcted heart and thereby impairing cardiac repair.…”

“…138 mPGES-1 inhibition, but not celecoxib, improves cardiac fibrosis and reduces infarct size after MI, 139 due to the shunting of PGH 2 to the cardioprotective PGI 2 . 139,140…”

Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases

“…64,149 A recent study found that urine PGI2 content was positively correlated with cardiac ejection fraction after MI, and PGI2 played a protective role in cardiac remodeling independently of PGE2. 150 Notably, the IP knockout mice showed increased infarct size after heart reperfusion injury, while TAX2 receptor (TP) knockout had no effect. 64 In addition, myocardial-produced PGI2 acts directly on cardiomyocytes to exert MIR-protective effects independent of the effects on centrocytes and platelets, 64 which may explain that TP-KO does not affect MIR-progression.…”