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

Author

Listed:
  • 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)

  • De-Pei Liu

    (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
    Chinese Academy of Medical Sciences and Peking Union Medical College)

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.

Suggested Citation

  • Liyuan Zhu & Chuansheng Xu & Xingyu Huo & Huifeng Hao & Qing Wan & Hong Chen & Xu Zhang & Richard M. Breyer & Yu Huang & Xuetao Cao & De-Pei Liu & Garret A. FitzGerald & Miao Wang, 2019. "The cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09492-4
    DOI: 10.1038/s41467-019-09492-4
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    Cited by:

    1. Pengfei Xu & Yingjie Zhang & Junyan Guo & Huihui Li & Sandra Konrath & Peng Zhou & Liming Cai & Haojie Rao & Hong Chen & Jian Lin & Zhao Cui & Bingyang Ji & Jianwei Wang & Nailin Li & De-Pei Liu & Tho, 2024. "A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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