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 PGE2 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.
Highlights
The use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX)-1 and COX-2, increases heart failure risk
Cox-1 KO and Cox-2 KO mice and their littermates were subjected to 30-min ischemia by ligating the left anterior descending coronary artery, followed by 24-h reperfusion
MI/R increased urinary excretion of PGE2 metabolites, which was mainly produced by COX-1, not COX-2 (Supplementary Fig. 1A, B)
Summary
The use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX)-1 and COX-2, increases heart failure risk. Cox-1 KO and Cox-2 KO mice and their littermates were subjected to 30-min ischemia by ligating the left anterior descending coronary artery, followed by 24-h reperfusion. Tissue levels of ATP in the area of myocardium at risk after I/R were reduced in mPges-1 KO mice (Fig. 2h) while the ratio of ADP to ATP was increased (Supplementary Fig. 4A, B).
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