Abstract 270: Microsomal Prostaglandin E Synthase-1 and Endothelial EP4 Receptor Reduces Myocardial Ischemia-reperfusion Injury via Improving Microcirculatory Perfusion
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...
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Published in | Arteriosclerosis, thrombosis, and vascular biology Vol. 38; no. Suppl_1 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
01.05.2018
|
Online Access | Get full text |
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Summary: | 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 |
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ISSN: | 1079-5642 1524-4636 |
DOI: | 10.1161/atvb.38.suppl_1.270 |