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

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.