Propofol Induces Cardioprotection Against Ischemia-Reperfusion Injury via Suppression of Transient Receptor Potential Vanilloid 4 Channel

Abstract

Ca²⁺ entry <i>via</i> the transient receptor potential vanilloid 4 (TRPV4) channel contributes to Ca²⁺ overload and triggers many pathophysiological conditions, including myocardial ischemia/reperfusion (I/R) injury. Propofol, a widely used intravenous anesthetic, attenuates myocardial I/R injury. However, the mechanism of propofol remains to be examined. The present study aims to test the hypothesis that propofol attenuates myocardial I/R injury through the suppression of TRPV4. We used a murine <i>ex vivo</i> model of myocardial I/R and <i>in vitro</i> cultured myocytes subjected to hypoxia/reoxygenation (H/R). Propofol or TRPV4 antagonist, HC-067047, attenuates myocardial I/R injury in isolated hearts. In addition, propofol, HC-067047, or TRPV4-siRNA attenuates H/R-induced intracellular Ca²⁺ concentration ([Ca²⁺]_i) increase and cell viability reduction. On the contrary, TRPV4 agonist GSK1016790A exacerbates both <i>ex vivo</i> and <i>in vitro</i> myocardial injury. Pretreatment with propofol reverses the myocardial injury and intracellular Ca²⁺ overload induced by GSK1016790A at least <i>in vitro</i>. However, neither the combination of propofol and HC-067047 nor applying propofol to cells transfected with TRPV4-siRNA creates additional protective effects. In addition, propofol dose-dependently inhibits TRPV4-mediated Ca²⁺ entry induced by GSK1016790A and 4α-PDD. Propofol attenuates myocardial I/R injury partially through the suppression of TRPV4 channel and the subsequent inhibition of intracellular Ca²⁺ overload.