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European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Sleep Apnea | Research

Autophagy impairment in patients with obstructive sleep apnea modulates intermittent hypoxia-induced oxidative stress and cell apoptosis via hypermethylation of the ATG5 gene promoter region

Authors: Yung-Che Chen, I-Chun Lin, Mao-Chang Su, Po-Yuan Hsu, Chang-Chun Hsiao, Te-Yao Hsu, Chia-Wei Liou, Yu-Mu Chen, Chien-Hung Chin, Ting-Ya Wang, Jen-Chieh Chang, Yong-Yong Lin, Chiu-Ping Lee, Meng-Chih Lin

Published in: European Journal of Medical Research | Issue 1/2023

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Abstract

Background

Autophagy is a catabolic process that recycles damaged organelles and acts as a pro-survival mechanism, but little is known about autophagy dysfunction and epigenetic regulation in patients with obstructive sleep apnea (OSA).

Methods

Protein/gene expressions and DNA methylation levels of the autophagy-related genes (ATG) were examined in blood leukocytes from 64 patients with treatment-naïve OSA and 24 subjects with primary snoring (PS).

Results

LC3B protein expression of blood monocytes, and ATG5 protein expression of blood neutrophils were decreased in OSA patients versus PS subjects, while p62 protein expression of cytotoxic T cell was increased, particularly in those with nocturia. ATG5, ULK1, and BECN1 gene expressions of peripheral blood mononuclear cells were decreased in OSA patients versus PS subjects. LC3B gene promoter regions were hypermethylated in OSA patients, particularly in those with excessive daytime sleepiness, while ATG5 gene promoter regions were hypermethylated in those with morning headache or memory impairment. LC3B protein expression of blood monocytes and DNA methylation levels of the LC3B gene promoter region were negatively and positively correlated with apnea hyponea index, respectively. In vitro intermittent hypoxia with re-oxygenation exposure to human THP-1/HUVEC cell lines resulted in LC3B/ATG5/ULK1/BECN1 down-regulations and p62 up-regulation along with increased apoptosis and oxidative stress, while rapamycin and umbilical cord-mesenchymal stem cell treatment reversed these abnormalities through de-methylation of the ATG5 gene promoter.

Conclusions

Impaired autophagy activity in OSA patients was regulated by aberrant DNA methylation, correlated with clinical phenotypes, and contributed to increased cell apoptosis and oxidative stress. Autophagy enhancers may be novel therapeutics for OSA-related neurocognitive dysfunction.
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Metadata
Title
Autophagy impairment in patients with obstructive sleep apnea modulates intermittent hypoxia-induced oxidative stress and cell apoptosis via hypermethylation of the ATG5 gene promoter region
Authors
Yung-Che Chen
I-Chun Lin
Mao-Chang Su
Po-Yuan Hsu
Chang-Chun Hsiao
Te-Yao Hsu
Chia-Wei Liou
Yu-Mu Chen
Chien-Hung Chin
Ting-Ya Wang
Jen-Chieh Chang
Yong-Yong Lin
Chiu-Ping Lee
Meng-Chih Lin
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01051-4

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