Abstract 270: Microsomal Prostaglandin E Synthase-1 and Endothelial EP4 Receptor Reduces Myocardial Ischemia-reperfusion Injury via Improving Microcirculatory Perfusion

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 38; no. Suppl_1
• Main Authors: Zhu, Liyuan, Xu, Chuansheng, Hao, Huifeng, Hu, Sheng, Wan, Qing, Wang, Miao
• Format: Journal Article
• Language: English
• Published: 01.05.2018
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/atvb.38.suppl_1.270

Abstract only Objective: Myocardial (M) ischemia/reperfusion (I/R) injury limits the efficacy of reperfusion therapy in patients with myocardial infarction (MI) and contributes to the development of heart failure. Nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit both cyclooxygenase (COX)-1 and COX-2, or those selective for COX-2 inhibition, are associated with an increased risk of heart failure. Although suppression of COX-2-derived prostaglandin (PG) I 2 predisposes cardiovascular risks, it remains unknown whether microsomal (m) PGE synthase (S)-1, a therapeutic target alternative to COX-2, might participate in MI/R injury. Approach and Results: Mice deficient in COX-1 or -2, mPGES-1, or endothelial PGE receptor-4 (EP4), together with pharmacological interventions, were utilized in a mouse model of MI/R. Microvascular perfusion was assessed in vivo using laser Doppler flow technique. COX-1 deficiency reduced biosynthesis of PGE 2 and increased infarct size in the heart after MI/R. Deletion of mPGES-1 also depressed PGE 2 while exacerbated MI/R injury. Cardiac perfusion was impaired by mPGES-1 deletion following reperfusion, without change in baseline flow. Consistently, mPGES-1 deletion abolished arteriolar dilation in I/R, and mPGES-1-derived PGE 2 acting on EP4 receptor restrains myeloid cell adhesion to endothelial cells in vitro and limits leukocyte adhesion to vasculature in I/R in vivo. Endothelium-restricted deletion of EP4 receptor impaired microcirculatory perfusion and exacerbated cardiac injury in MI/R. By contrast, treatment with misoprostol, a clinically available PGE 2 analogue, improved cardiac microcirculation post MI and protected against I/R injury. Conclusions: mPGES-1-derived PGE 2 and endothelial EP4 receptor protect against MI/R injury via preserving cardiac microcirculation. mPGES-1 inhibitors may harm microcirculation in patients with acute MI undergoing revascularization. Inhibition of COX-1-derived PGE 2 may contribute to the cardiovascular side effects of NSAIDs in the setting of I/R. Key Words: myocardial infarction, ischemia reperfusion, cyclooxygenase, prostaglandin E synthase-1, PGE 2 , EP4, microcirculation, endothelium