{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:48:39Z","timestamp":1790704119398,"version":"4.1.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2017,5,25]],"date-time":"2017-05-25T00:00:00Z","timestamp":1495670400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,25]],"date-time":"2017-05-25T00:00:00Z","timestamp":1495670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Transient receptor potential vanilloid 4 (TRPV4) is highly expressed in heart and vessels and can be activated during myocardial ischemia\/reperfusion (I\/R). Recently, we found that treatment with a selective TRPV4 antagonist HC-067047 significantly reduced infarct size, decreased troponin T levels and improved cardiac function in murine model myocardial I\/R. This study was undertaken to investigate the mechanism underlying TRPV4-mediated myocardial I\/R injury. To mimic myocardial I\/R injury, we established a hypoxia\/reoxygenation (H\/R) model in H9C2 cells and neonatal rat ventricle myocytes (NRVMs) <jats:italic>in vitro<\/jats:italic>. TRPV4 mRNA and protein expression was confirmed in the H9C2 and NRVM, whereas functional TRPV4 activity was assessed from Ca<jats:sup>2+<\/jats:sup> influx response to a TRPV4 agonist GSK1016790A. TRPV4 functional expression was significantly enhanced during H\/R. Furthermore, H\/R increased the intracellular Ca<jats:sup>2+<\/jats:sup> concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) and induced cell injury, which were reversed by HC-067047 but was further aggravated by GSK1016790A. Moreover, HC-067047 treatment significantly alleviated the increase of reactive oxygen species (ROS) generation, the depolarization of mitochondrial membrane potential (\u0394\u03c8m) and the opening of mitochondrial permeability transition pore (mPTP) during H\/R. On the contrary, GSK1016790A exacerbated those effects. Meanwhile, increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and ROS induced by activation of TRPV4 was almost abolished when cells were cultured in Ca<jats:sup>2+<\/jats:sup>-free medium. In addition, ROS scavenger NAC obviously reversed activation of TRPV4-induced changes of \u0394\u03c8m and mPTP opening. Finally, we confirmed the direct roles of TRPV4 on cardiac injury and ROS generation in murine model myocardial I\/R <jats:italic>in vivo<\/jats:italic>. In conclusion, activation of TRPV4 induces Ca<jats:sup>2+<\/jats:sup> influx in cardiomyocytes, with subsequent ROS release, depolarizing of \u0394\u03c8m, opening mPTP, inducing injury and TRPV4 has key roles during I\/R via these pathways.<\/jats:p>","DOI":"10.1038\/cddis.2017.227","type":"journal-article","created":{"date-parts":[[2017,5,25]],"date-time":"2017-05-25T16:54:22Z","timestamp":1495731262000},"page":"e2828-e2828","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Activation of transient receptor potential vanilloid 4 involves in hypoxia\/reoxygenation injury in cardiomyocytes"],"prefix":"10.1038","volume":"8","author":[{"given":"Qiong-Feng","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin-Bin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixiu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Mei","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hua","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,25]]},"reference":[{"key":"BFcddis2017227_CR1","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1038\/35036318","volume":"2","author":"R Strotmann","year":"2000","unstructured":"Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD . 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