Abstract
Antioxidative stress provides a cardioprotective effect during myocardial ischemia/reperfusion (I/R). Previous research has demonstrated that the blockade of transient receptor potential vanilloid 4 (TRPV4) attenuates myocardial I/R injury. However, the underlying mechanism remains unclear. The current study is aimed at investigating the antioxidative activity of TRPV4 inhibition and elucidating the underlying mechanisms in vitro and ex vivo. We found that the inhibiting TRPV4 by the selective TRPV4 blocker HC-067047 or specific TRPV4-siRNA significantly reduces reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels in H9C2 cells exposed to hypoxia/reoxygenation (H/R). Meanwhile, the activity of antioxidative enzymes, particularly superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), is enhanced. Furthermore, after H/R, HC-067047 treatment increases the expression of P-Akt and the translocation of nuclear factor E2-related factor 2 (Nrf2) and related antioxidant response element (ARE) mainly including SOD, GSH-Px, and catalase (CAT). LY294002, an Akt inhibitor, suppresses HC-067047 and specific TRPV4-siRNA-induced Nrf2 expression and its nuclear accumulation. Nrf2 siRNA attenuates HC-067047 and specific TRPV4-siRNA-induced ARE expression. In addition, treatment with LY294002 or Nrf2 siRNA significantly attenuates the antioxidant and anti-injury effects of HC-067047 in vitro. Finally, in experiments on isolated rat hearts, we confirmed the antioxidative stress roles of TRPV4 inhibition during myocardial I/R and the application of exogenous H2O2. In conclusion, the inhibition of TRPV4 exerts cardioprotective effects through enhancing antioxidative enzyme activity and expressions via the Akt/Nrf2/ARE pathway.
Highlights
Ischemia/reperfusion (I/R) injury is the leading factor that aggravates myocardial dysfunction and cardiomyocyte death after cardiac surgery and myocardial infarction [1]
We demonstrated that the activation of transient receptor potential vanilloid 4 (TRPV4) induces myocardial injury through increasing oxidative stress during H/R [16]
These results suggest that the inhibition of TRPV4 reduces the levels of reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) in H9C2 cells exposed to H/R
Summary
Ischemia/reperfusion (I/R) injury is the leading factor that aggravates myocardial dysfunction and cardiomyocyte death after cardiac surgery and myocardial infarction [1]. It is noteworthy that the accumulation of intracellular ROS can lead to apoptotic cell death [4] and has a direct effect on myocardial structure and function [5]. The activation of endogenous antioxidant defense likely ameliorates myocardial I/R injury. Nuclear factor-erythroid 2-related factor 2 (Nrf2), as a redox-sensitive transcription factor, regulates the cellular antioxidant defense system by binding to antioxidant response elements (AREs) in their promoter regions [6]. The phosphorylation of Akt has been shown to alleviate oxidative stress injury through promoting the activation of Nrf2/ARE signaling [9, 10]. Akt/Nrf2/ARE might be a valuable therapeutic target for the prevention of myocardial I/R-induced oxidative stress and damage
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