title: 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-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.
authors.affiliation: 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Qiong-Feng
authors.initials: QF
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.affiliation: 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.
authors.forename: Dan
authors.initials: D
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Bin-Bin
authors.initials: BB
authors.lastname: Wang
authors.affiliation: Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Ke-Fang
authors.initials: KF
authors.lastname: Guo
authors.affiliation: Department of Orhtopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, Hubei, 430022, P.R. China.
authors.forename: Dehao
authors.initials: D
authors.lastname: Fu
authors.affiliation: Department of Cardiology, Xuzhou Central Hospital, Jiefang Nan Lu 199, Xuzhou, Jiangsu 221009, P.R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Liao
authors.affiliation: 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.
authors.forename: Yi-Mei
authors.initials: YM
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D055786:Gene Knockout Techniques; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006334:Heart Function Tests; D051379:Mice; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism
chemical_list: C573308:HC-067047; D009025:Morpholines; D011758:Pyrroles; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt