The cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury

Abstract

The use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX)-1 and COX-2, increases heart failure risk. It is unknown whether microsomal (m) prostaglandin (PG) E synthase (S)-1, a target downstream of COX, regulates myocardial (M) ischemia/reperfusion (I/R) injury, a key determinant of heart failure. Here we report that COX-1 and mPGES-1 mediate production of substantial amounts of PGE 2 and confer cardiac protection in MI/R. Deletion of mPges-1 impairs cardiac microvascular perfusion and increases inflammatory cell infiltration in mouse MI/R. Consistently, mPges-1 deletion depresses the arteriolar dilatory response to I/R in vivo and to acetylcholine ex vivo, and enhances leukocyte-endothelial cell interaction, which is mediated via PGE receptor-4 (EP4). Furthermore, endothelium-restricted Ep4 deletion impairs microcirculation, and exacerbates MI/R injury, irrespective of EP4 agonism. Treatment with misoprostol, a clinically available PGE analogue, improves microcirculation and reduces MI/R injury. Thus, mPGES-1, a key microcirculation protector, constrains MI/R injury and this beneficial effect is partially mediated via endothelial EP4.

Exploring Molecular Mechanism of Huangqi in Treating Heart Failure Using Network Pharmacology

“…Elevation of IL-6 and IL-1β can induce cardiomyocyte apoptosis and reduce ventricular wall compliance and cause coronary microvascular endothelial inflammation [42]. Study shows that the use of nonsteroidal anti-inflammatory drugs that inhibit PTGS1 and PTGS2 increases the risk of HF as they can reduce prostaglandin E generation that can protect the heart [43]. Both ADRA2C and ADRB1 are involved in the regulation of myocardial contractility, heart rate, and blood pressure [44].…”

Microsomal Prostaglandin E2 Synthase-1 Deletion Attenuates Isoproterenol-Induced Myocardial Fibrosis in Mice

“…However, the role of mPGES-1 in pathological cardiac remodeling and heart dysfunction is still in debate. Although studies had reported impaired post-ischemic heart function and cardiac remodeling in mPGES-1 deficient mice (Degousee et al, 2008;Zhu et al, 2019), we and others failed to observe any adverse influence on cardiac remodeling after mPGES-1 was deleted globally or selectively in myeloid cells (Chen et al, 2019;Wu et al, 2009b). Moreover, in a model of Ang II mediated cardiac remodeling, although lack of mPGES-1 did not affect cardiac hypertrophy and fibrosis, nevertheless poor cardiac function was observed (Harding, Yang, He, & This article has not been copyedited and formatted.…”

Co‑expression of tissue kallikrein 1 and tissue inhibitor of matrix metalloproteinase 1 improves myocardial ischemia‑reperfusion injury by promoting angiogenesis and inhibiting oxidative stress

“…Myocardial I/R injury protocol. The induction of myocardial I/R injury in the present study was performed as previously described (17), with a few modifications. Briefly, rats were anesthetized by the intraperitoneal injection of pentobarbital sodium (40 mg/kg) and were mechanically ventilated.…”