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

Binbin Wang,Qian Dong,Ning Zhao,Cui Yang,Shaoshao Zhang,Jie Liao,Zhengrong Huang,Yimei Du,Kefang Guo,Huixia Liu,Qiongfeng Wu

doi:10.3389/fphar.2019.01150

Abstract

Ca2+ entry via 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 ex vivo model of myocardial I/R and in vitro 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 ex vivo and in vitro myocardial injury. Pretreatment with propofol reverses the myocardial injury and intracellular Ca2+ overload induced by GSK1016790A at least in vitro. 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.

Highlights

Propofol (2, 6-diisopropylphenol), an intravenous anesthetic frequently used during surgery, has been proved to dose-dependently attenuate myocardial ischemia/reperfusion (I/R) and hypoxia/ reoxygenation (H/R) injury (Xia et al, 2006; Sun et al, 2017; Zhao et al, 2019)
One of our recent studies has shown that Ca2+ entry via the transient receptor potential vanilloid 4 (TRPV4) channel in cardiomyocytes plays a critical role in mediating Ca2+ overload and reactive oxygen species (ROS) release during the process of myocardial I/R injury (Wu et al, 2017)
Earlier studies have demonstrated that propofol protects the heart against I/R injury through inhibiting intracellular Ca2+ overload (Kim et al, 2008)

Summary

Introduction

Propofol (2, 6-diisopropylphenol), an intravenous anesthetic frequently used during surgery, has been proved to dose-dependently attenuate myocardial ischemia/reperfusion (I/R) and hypoxia/ reoxygenation (H/R) injury (Xia et al, 2006; Sun et al, 2017; Zhao et al, 2019). Excessive Ca2+ influx through TRPV4 induced by TRPV4 agonists GSK1016790A and 4α-PDD leads to the apoptosis of retinal ganglion cells and neuronal death in the hippocampus (Ryskamp et al, 2011; Jie et al, 2016) Based on these findings, TRPV4 channel is a promising target in the treatment of I/R-induced myocardial injury (Jones et al, 2019; Wu et al, 2019). In this study, we hypothesize that propofol activates protective mechanisms through the suppression of TRPV4 channel and the subsequent inhibition of intracellular Ca2+ overload in ex vivo isolated hearts under I/R and in vitro cell models under H/R

Methods

Results

Conclusion