title: Upregulated ATF6 contributes to chronic intermittent hypoxia-afforded protection against myocardial ischemia/reperfusion injury.
abstract: In the present study, we investigated the role of activating transcription factor 6 (ATF6) in the mechanism by which chronic intermittent hypoxia (CIH) increases tolerance to myocardial ischemia/reperfusion (I/R). Experiments were conducted using a rat model of I/R injury in vivo and isolated Langendorff-perfused rat hearts ex vivo. The role of Akt in this process was also investigated in vitro using rat myoblast H9c2 cells. Cell viability was measured using a cell counting kit-8 assay. Lactate dehydrogenase (LDH) and creatine kinase cardiac isoenzyme activity were also measured as markers of cellular damage. ATF6, Akt and phosphorylated (p)-Akt expression was analyzed by western blot analysis. RNA interference (RNAi) was used to suppress ATF6 expression. We noted that ATF6 expression in the ventricular myocardium was significantly increased in rats exposed to CIH. Furthermore, we noted that CIH preserved cardiac function after I/R in vivo and improved post-ischemic recovery of myocardial performance in isolated rat hearts. ATF6 and p-Akt expression was upregulated in cultured H9c2 cells exposed to chronic mild hypoxia compared with those cultured under normoxic conditions. Chronic mild hypoxia attenuated subsequent simulated I/R injury in H9c2 cells (48 h), as evidenced by increased cell viability and decreased LDH activity. By contrast, decreased cell viability and increased LDH activity were observed in siRNA-ATF6-transfected H9c2 cells, with a concomitant reduction in p-Akt levels. These results indicated that ATF6 upregulation is involved in the mechanism by which CIH attenuates myocardial I/R injury, possibly through upregulation of p-Akt, which is a key regulator of cardiomyocyte survival.
authors.affiliation: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Weikun
authors.initials: W
authors.lastname: Jia
authors.affiliation: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Jian
authors.affiliation: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Fuqin
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Xiao
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D016277:Ventricular Function, Left
chemical_list: D051702:Activating Transcription Factor 6; D051057:Proto-Oncogene Proteins c-akt