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

The Ca2+-permeable TRPV4 cation channel is expressed in neutrophils and contributes to myocardial ischemia/reperfusion injury. Here we tested the hypotheses that TRPV4 promotes neutrophil activation and subsequently aggregates myocardial ischemia/reperfusion 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-dependently promoted migration toward fMLP, reactive oxygen species production, and myeloperoxidase release, which were prevented by pretreatment with a selective TRPV4 antagonist, in neutrophils from TRPV4 knockout mice, Ca2+-free medium, or BAPTA-AM + Ca2+-free medium. Blockade of TRPV4 also inhibited the effects of commonly used neutrophil activators fMLP and PMA. Mechanically, TRPV4 regulated neutrophil activation, particularly reactive oxygen species production, by affecting PKC & alpha;, P38, and AKT via Ca2+ signaling. In addition, isolated hearts infused with neutrophils from wild-type mice showed additional myocardial ischemia/reperfusion injuries but not those infused with TRPV4 knockout. Our study reveals that TRPV4-mediated neutrophil activation enhances myocardial ischemia/reperfusion injury, and it might be a novel therapeutic target for myocardial ischemia/reperfusion injury and other neutrophil-mediated inflammatory diseases. Mechanisms of how neutrophils are modulated by transient receptor potential vanilloid 4 and implications on myocardial ischemia/reperfusion injury. Graphical abstract