Chronic intermittent hypoxia induces cardiac hypertrophy by impairing autophagy through the adenosine 5'-monophosphate-activated protein kinase pathway.
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.
['Xie|Sheng|S|', 'Deng|Yan|Y|', 'Pan|Yue-Ying|YY|', 'Ren|Jie|J|', 'Jin|Meng|M|', 'Wang|Yu|Y|', 'Wang|Zhi-Hua|ZH|', 'Zhu|Die|D|', 'Guo|Xue-Ling|XL|', 'Yuan|Xiao|X|', 'Shang|Jin|J|', 'Liu|Hui-Guo|HG|']
D055372:AMP-Activated Protein Kinases D000255:Adenosine Triphosphate D000263:Adenylate Kinase D000818:Animals D017209:Apoptosis D001343:Autophagy D000071187:Autophagy-Related Protein 5 D019703:Calcineurin D006332:Cardiomegaly D006439:Hemodynamics D000860:Hypoxia D008297:Male D046529:Microscopy, Electron, Transmission D009206:Myocardium D010766:Phosphorylation D034622:RNA Interference D051381:Rats D017207:Rats, Sprague-Dawley D020123:Sirolimus
Chronic intermittent hypoxia Cardiac hypertrophy Autophagy Adenosine monophosphate-activated protein kinase