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

Liyuan Zhu, Chuansheng Xu, Xingyu Huo, Huifeng Hao, Qing Wan, Hong Chen, Xu Zhang, Richard M. Breyer, Yu Huang, Xuetao Cao, Liu De-Pei, Garret A. FitzGerald and Miao Wang ()
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Liyuan Zhu: Chinese Academy of Medical Sciences and Peking Union Medical College
Chuansheng Xu: Chinese Academy of Medical Sciences and Peking Union Medical College
Xingyu Huo: Chinese Academy of Medical Sciences and Peking Union Medical College
Huifeng Hao: Chinese Academy of Medical Sciences and Peking Union Medical College
Qing Wan: Chinese Academy of Medical Sciences and Peking Union Medical College
Hong Chen: Chinese Academy of Medical Sciences and Peking Union Medical College
Xu Zhang: Tianjin Medical University
Richard M. Breyer: Vanderbilt University Medical Center
Yu Huang: The Chinese University of Hong Kong
Xuetao Cao: Chinese Academy of Medical Sciences and Peking Union Medical College
Liu De-Pei: Chinese Academy of Medical Sciences and Peking Union Medical College
Garret A. FitzGerald: University of Pennsylvania
Miao Wang: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09492-4

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