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Abstract
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) in vitro. TRPV4 mRNA and protein expression was confirmed in the H9C2 and NRVM, whereas functional TRPV4 activity was assessed from Ca2+ influx response to a TRPV4 agonist GSK1016790A. TRPV4 functional expression was significantly enhanced during H/R. Furthermore, H/R increased the intracellular Ca2+ concentration ([Ca2+]i) 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 (Δψm) and the opening of mitochondrial permeability transition pore (mPTP) during H/R. On the contrary, GSK1016790A exacerbated those effects. Meanwhile, increase in [Ca2+]i and ROS induced by activation of TRPV4 was almost abolished when cells were cultured in Ca2+-free medium. In addition, ROS scavenger NAC obviously reversed activation of TRPV4-induced changes of Δψm and mPTP opening. Finally, we confirmed the direct roles of TRPV4 on cardiac injury and ROS generation in murine model myocardial I/R in vivo. In conclusion, activation of TRPV4 induces Ca2+ influx in cardiomyocytes, with subsequent ROS release, depolarizing of Δψm, opening mPTP, inducing injury and TRPV4 has key roles during I/R via these pathways.
Highlights
Transient receptor potential vanilloid 4 (TRPV4) is highly expressed in heart and vessels and can be activated during myocardial ischemia/reperfusion (I/R)
To further test whether TRPV4 is functionally active in cardiomyocytes, we loaded H9C2 and neonatal rat ventricle myocytes (NRVMs) with Fluo-4/AM and measured Ca2+ influx in response to the specific TRPV4 agonist, GSK1016790A
Our results show that TRPV4 is functionally expressed in cardiomyocytes
Summary
Transient receptor potential vanilloid 4 (TRPV4) is highly expressed in heart and vessels and can be activated during myocardial ischemia/reperfusion (I/R). During myocardial ischemia/reperfusion (I/R), TRPV4 may be overactivated by cytotoxic edema or the metabolites of arachidonic acid, and it involves in myocardial I/R injury.[5,6] our previous study has demonstrated 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.7. Activation of TRPV4 elicits Ca2+ influx and increases the intracellular concentration of free Ca2+ ([Ca2+]i).[1,14] recent studies have found that TRPV4 agonists enhances the production of reactive oxygen species (ROS) via Ca2+ influx in endothelial cells, urothelial cell, macrophages, as well as hippocampus.[15,16,17,18] In addition, Ca2+ overload and high level of ROS can trigger depolarization of mitochondrial membrane potential (Δψm), Central Hospital, Xuzhou, China. Some of the results were confirmed in the murine model myocardial I/R in vivo
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