Sleep Disorders: Sleep Disorders III |

Impaired Autophagy Contributes to Hypertrophic Cardiomyopathy Induced by Chronic Intermittent Hypoxia FREE TO VIEW

Sheng Xie; Huiguo Liu
Author and Funding Information

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China

Copyright 2016, American College of Chest Physicians. All Rights Reserved.

Chest. 2016;149(4_S):A576. doi:10.1016/j.chest.2016.02.601
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SESSION TITLE: Sleep Disorders III

SESSION TYPE: Original Investigation Poster

PRESENTED ON: Saturday, April 16, 2016 at 11:45 AM - 12:45 PM

PURPOSE: Myocardial autophagy is activated by chronic intermittent hypoxia (CIH), but the dynamics and functional roles of autophagy are unclear. Here we investigated the dynamics of myocardial autophagy and examined its role during cardiomyopathy induced by CIH.

METHODS: Methods and results: Cardiac hypertrophy was induced in vivo by CIH for up to 10 weeks. Autophagy was assessed by measuring changes in Beclin-1, LC3 cleavage, and ultrastructural autophagosomes. We also measured changes in the activation of AMP-activated protein kinase, a critical myocardial autophagy regulator. The results approximately indicates a sharply retreatment of autophagy after a compensate increasing. We further identify the autophagy impairment by autophagy flux assay with chloroquine or not. Cardiomyopathy in response to impaired autophagy was assessed by measuring serum atrial natriuretic peptide levels, heart/body weight ratios, cardiomyocyte size, fibrotic area, cardiomyocyte apoptosis, and the hemodynamic index. Rapamycin (an inducer of autophagy) can attenuated cardiomyopathy by restoring autophagy. 3-Methyladenine (an autophagy inhibitor) exerted the opposite effect. We compared AMPK activation under normoxia or CIH and detected AMPK inactivation during CIH. Then we dual-regulated AMPK activation and found a same changing trend of autophagy and AMPK activation in vivo. These results indicate that AMPK is a direct target under CIH which can induce autophagy impairment. Morphological and abundant changes in autophagosomes and changes in the expression of beclin1 and LC3 cleavage couple with the unchanging of Cathepsin D and p62 accumulation suggested that CIH mainly interfered with the initial step of autophagy which induces more cellular construct damage. Moreover, CIH induced impaired autophagy which decreased cell viability and ATP supply and increased cardiomyocyte apoptosis, indicating that impaired autophagy reduced cardiomyocyte survival. Rescue experiment with rapamycin will ameliorate these pathological changes while 3-MA will deteriorate them. Moreover, the similar function of AMPK further definite the autophagy regulating role of AMPK under CIH.

RESULTS: Demonstrated above.

CONCLUSIONS: Prolonged CIH treatment impairs autophagy through the AMPK pathway, which contributes to cardiomyopathy.

CLINICAL IMPLICATIONS: We highlighted the importance of autophagy against CIH and provide a new perspective for the potential treatment of CIH-induced cardiac hypertrophy.

DISCLOSURE: Sheng Xie: Other: This research was funded by the National Natural Science Foundation of PR China (grants 81370185 and 81070067). Huiguo Liu: Other: This research was funded by the National Natural Science Foundation of PR China (grants 81370185 and 81070067).

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