Transient receptor potential vanilloid 4 (TRPV4) in neutrophils enhances myocardial ischemia/reperfusion injury

  • J Leukoc Biol. 2023 May 26;qiad063. doi: 10.1093/jleuko/qiad063.
Yuwei Wu  1  2  3  4 ,  Kai Lu  1  2  3  4  5 ,  Yang Lu  1  2  3  4 ,  Jie Liao  1  2  3  4 ,  Shaoshao Zhang  1  2  3  4 ,  Shuaitao Yang  1  2  3  4 ,  Ning Zhao  1  2  3  4 ,  Qian Dong  1  2  3  4 ,  Lei Chen  6 ,  Qiongfeng Wu  1  2  3  4 ,  Yimei Du  1  2  3  4
Affiliations
  • 1. Department of Cardiology.
  • 2. Research Center of Ion Channelopathy.
  • 3. Hubei Key Laboratory of Biological Targeted Therapy.
  • 4. Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5. Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China.
  • 6. Department of Physiology, Nanjing Medical University, Nanjing, China.
PMID: 37232941 DOI: 10.1093/jleuko/qiad063
Abstract

The calcium (Ca2+) permeable transient receptor potential vanilloid 4 (TRPV4) cation channel is expressed in neutrophils and contributes to myocardial ischemia/reperfusion (I/R) injury. Here we tested the hypotheses that TRPV4 promotes neutrophil activation and subsequently aggregates myocardial I/R injury. TRPV4 protein was confirmed in neutrophils and its function was assessed by the current and intracellular Ca2+ concentration elevations evoked by TRPV4 agonists. Furthermore, TRPV4 agonists dose-repandly promoted migration toward fMLP, Reactive Oxygen Species (ROS) production, and myeloperoxidase (MPO) release, which were prevented by pretreatment with a selective TRPV4 antagonist, in neutrophils from TRPV4 knock-out (KO) mice, Ca2+-free medium, or BAPTA-AM + Ca2+-free medium. Blockade of TRPV4 also inhibited the effects of commonly used neutrophil activators N-formyl-l-methionyl-leucyl-l-phenylalanine (fMLP) and Phorbol 12-myristate 13-acetate (PMA). Mechanically, TRPV4 regulated neutrophil activation, particularly ROS production, by affecting PKCα, P38, and Akt via Ca2+ signaling. In addition, isolated hearts infused with neutrophils from wild-type (WT) mice showed additional myocardial I/R injuries, but not those infused with TRPV4 KO. Our study reveals that TRPV4-mediated neutrophil activation enhances myocardial I/R injury, and it might be a novel therapeutic target for myocardial I/R injury and Other neutrophil-mediated inflammatory diseases.

Keywords
calcium; neutrophil activation; reactive oxygen species.
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