title: Acute ethanol exposure-induced autophagy-mediated cardiac injury via activation of the ROS-JNK-Bcl-2 pathway.
abstract: Binge drinking is associated with increased cardiac autophagy, and often triggers heart injury. Given the essential role of autophagy in various cardiac diseases, this study was designed to investigate the role of autophagy in ethanol-induced cardiac injury and the underlying mechanism. Our study showed that ethanol exposure enhanced the levels of LC3-II and LC3-II positive puncta and promoted cardiomyocyte apoptosis in vivo and in vitro. In addition, we found that ethanol induced autophagy and cardiac injury largely via the sequential triggering of reactive oxygen species (ROS) accumulation, activation of c-Jun NH2-terminal kinase (JNK), phosphorylation of Bcl-2, and dissociation of the Beclin 1/Bcl-2 complex. By contrast, inhibition of ethanol-induced autophagic flux with pharmacologic agents in the hearts of mice and cultured cells significantly alleviated ethanol-induced cardiomyocyte apoptosis and heart injury. Elimination of ROS with the antioxidant N-acetyl cysteine (NAC) or inhibition of JNK with the JNK inhibitor SP600125 reduced ethanol-induced autophagy and subsequent autophagy-mediated apoptosis. Moreover, metallothionein (MT), which can scavenge reactive oxygen and nitrogen species, also attenuated ethanol-induced autophagy and cell apoptosis in MT-TG mice. In conclusion, our findings suggest that acute ethanol exposure induced autophagy-mediated heart toxicity and injury mainly through the ROS-JNK-Bcl-2 signaling pathway.
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Yewei
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The First Affiliated Hospital of Zhejiang Chinese Medical University, First Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, P. R. China.|Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, P. R. China.
authors.forename: Lingchun
authors.initials: L
authors.lastname: Lv
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Youli
authors.initials: Y
authors.lastname: Tao
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Minglong
authors.initials: M
authors.lastname: Shao
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Congcong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Xue
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Sun
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Niu
authors.affiliation: Department of Histology and Embryology, Institute of neuroscience, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung, Korea.
authors.forename: Sunam
authors.initials: S
authors.lastname: Kim
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Weitao
authors.initials: W
authors.lastname: Cong
authors.affiliation: The First Affiliated Hospital of Zhejiang Chinese Medical University, First Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Mao
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
authors.forename: Litai
authors.identifier: http://orcid.org/0000-0002-7598-5938
authors.initials: L
authors.lastname: Jin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002310:Cardiomyopathy, Alcoholic / Q000201:enzymology* / Q000473:pathology; D066126:Cardiotoxicity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000431:Ethanol; D020022:Genetic Predisposition to Disease; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000975:Antioxidants; C000617196:Bcl2 protein, rat; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C052617:Bcl2 protein, mouse; D000431:Ethanol; D048031:JNK Mitogen-Activated Protein Kinases
keywords: ROS-JNK; apoptosis; autophagy; cardiac function; ethanol