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Blockage of transient receptor potential vanilloid 4 alleviates myocardial ischemia/reperfusion injury in mice.


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-3?), 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.

SUBMITTER: Dong Q 

PROVIDER: S-EPMC5311718 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Blockage of transient receptor potential vanilloid 4 alleviates myocardial ischemia/reperfusion injury in mice.

Dong Qian Q   Li Jing J   Wu Qiong-Feng QF   Zhao Ning N   Qian Cheng C   Ding Dan D   Wang Bin-Bin BB   Chen Lei L   Guo Ke-Fang KF   Fu Dehao D   Han Bing B   Liao Yu-Hua YH   Du Yi-Mei YM  

Scientific reports 20170216


Transient receptor potential vanilloid 4 (TRPV4) is a Ca<sup>2+</sup>-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  ...[more]

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