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

  • Nat Commun. 2019 Apr 23;10(1):1888. doi: 10.1038/s41467-019-09492-4.
Liyuan Zhu  1 ,  Chuansheng Xu  1 ,  Xingyu Huo  1 ,  Huifeng Hao  1 ,  Qing Wan  1 ,  Hong Chen  1 ,  Xu Zhang  2 ,  Richard M Breyer  3 ,  Yu Huang  4 ,  Xuetao Cao  5 ,  De-Pei Liu  5 ,  Garret A FitzGerald  6 ,  Miao Wang  7  8
Affiliations
  • 1. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
  • 2. Tianjin Key Laboratory of Metabolic Diseases and Department of Physiology, Tianjin Medical University, Tianjin, 300070, China.
  • 3. Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37212, USA.
  • 4. Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 5. Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
  • 6. Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 7. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. [email protected].
  • 8. Clinical Pharmacology Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. [email protected].
PMID: 31015404 DOI: 10.1038/s41467-019-09492-4
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.

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