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Sci Rep. 2017 Feb 16;7:42678. doi: 10.1038/srep42678.

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

Author information

1
Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, Hubei, 430022, P.R. China.
2
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, P.R. China.
3
Department of anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
4
Department of Orhtopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, Hubei, 430022, P.R. China.
5
Department of Cardiology, Xuzhou Central Hospital, Jiefang Nan Lu 199, Xuzhou, Jiangsu 221009, P.R. China.

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.

PMID:
28205608
PMCID:
PMC5311718
DOI:
10.1038/srep42678
[Indexed for MEDLINE]
Free PMC Article

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