title: Chronic intermittent hypoxia induces cardiac hypertrophy by impairing autophagy through the adenosine 5'-monophosphate-activated protein kinase pathway.
abstract: Autophagy is tightly regulated to maintain cardiac homeostasis. Impaired autophagy is closely associated with pathological cardiac hypertrophy. However, the relationship between autophagy and cardiac hypertrophy induced by chronic intermittent hypoxia (CIH) is not known. In the present study, we measured autophagy-related genes and autophagosomes during 10 weeks of CIH in rats, and 6 days in H9C2 cardiomyocytes, and showed that autophagy was impaired. This conclusion was confirmed by the autophagy flux assay. We detected significant hypertrophic changes in myocardium with impaired autophagy. Rapamycin, an autophagy enhancer, attenuated the cardiac hypertrophy induced by CIH. Moreover, silencing autophagy-related gene 5 (ATG5) exerted the opposite effect. The role of adenosine monophosphate-activated protein kinase (AMPK) in regulating autophagy under CIH was confirmed using AICAR to upregulate this enzyme and restore autophagy flux. Restoring autophagy by AICAR or rapamycin significantly reversed the hypertrophic changes in cardiomyocytes. To investigate the mechanism of autophagy impairment, we compared phospho (p)-AMPK, p-Akt, cathepsin D, and NFAT3 levels, along with calcineurin activity, between sham and CIH groups. CIH activated calcineurin, and inhibited AMPK and AMPK-mediated autophagy in an Akt- and NFAT3-independent manner. Collectively, these data demonstrated that impaired autophagy induced by CIH through the AMPK pathway contributed to cardiac hypertrophy.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xie
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Yue-Ying
authors.initials: YY
authors.lastname: Pan
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Die
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Xue-Ling
authors.initials: XL
authors.lastname: Guo
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Shang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, China. Electronic address: hgliu@tjh.tjmu.edu.cn.
authors.forename: Hui-Guo
authors.initials: HG
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology*; D006439:Hemodynamics; D000860:Hypoxia; D008297:Male; D046529:Microscopy, Electron, Transmission; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000737:chemistry
chemical_list: C545865:Atg5 protein, rat; D000071187:Autophagy-Related Protein 5; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase; D019703:Calcineurin; D020123:Sirolimus
keywords: Adenosine monophosphate-activated protein kinase; Autophagy; Cardiac hypertrophy; Chronic intermittent hypoxia