Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable nonselective cation channel and can be activated during ischemia/reperfusion (I/R). This study tested whether blockade of TRPV4 can alleviate myocardial I/R injury in mice. TRPV4 expression began to increase at 1 h, reached statistically at 4 h, and peaked at 24–72 h. Treatment with the selective TRPV4 antagonist HC-067047 or TRPV4 knockout markedly ameliorated myocardial I/R injury as demonstrated by reduced infarct size, decreased troponin T levels and improved cardiac function at 24 h after reperfusion. Importantly, the therapeutic window for HC-067047 lasts for at least 12 h following reperfusion. Furthermore, treatment with HC-067047 reduced apoptosis, as evidenced by the decrease in TUNEL-positive myocytes, Bax/Bcl-2 ratio, and caspase-3 activation. Meanwhile, treatment with HC-067047 attenuated the decrease in the activation of reperfusion injury salvage kinase (RISK) pathway (phosphorylation of Akt, ERK1/2, and GSK-3β), while the activation of survival activating factor enhancement (SAFE) pathway (phosphorylation of STAT3) remained unchanged. In addition, the anti-apoptotic effects of HC-067047 were abolished by the RISK pathway inhibitors. We conclude that blockade of TRPV4 reduces apoptosis via the activation of RISK pathway, and therefore might be a promising strategy to prevent myocardial I/R injury.
Highlights
Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable nonselective cation channel and can be activated during ischemia/reperfusion (I/R)
To test the involvement of TRPV4 in myocardial I/R injury, we examined the TRPV4 expression levels in the heart at different reperfusion time points after 30 min ischemia (Supplement Fig. 1A)
Similar results were observed on TRPV4 protein abundance except that TRPV4 protein expression seems to peak at 72 h (Fig. 1B)
Summary
Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable nonselective cation channel and can be activated during ischemia/reperfusion (I/R). We conclude that blockade of TRPV4 reduces apoptosis via the activation of RISK pathway, and might be a promising strategy to prevent myocardial I/R injury. There is new increasing evidence that several cation-permeable transient receptor potential (TRP) channels, vanilloid (TRPV) subfamily, can influence physiological systems compromised in myocardial I/R injury, and may represent potential therapeutic targets[4,5,6]. TRPV4 channel, mainly for Ca2+ permeate, is widely distributed in various organs and tissues including heart and vessels[7,8] It can be activated by a variety of physical and chemical stimuli, including hypotonic stimulation, cell swelling, moderate heat (>24–37 °C), and endogenous metabolites of arachidonic acid[9,10].
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