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

• Published in: European journal of medical research 2023-02, Vol.28 (1), p.82-82, Article 82
• Main Authors: Chen, Yung-Che, Lin, I-Chun, Su, Mao-Chang, Hsu, Po-Yuan, Hsiao, Chang-Chun, Hsu, Te-Yao, Liou, Chia-Wei, Chen, Yu-Mu, Chin, Chien-Hung, Wang, Ting-Ya, Chang, Jen-Chieh, Lin, Yong-Yong, Lee, Chiu-Ping, Lin, Meng-Chih
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - genetics; Autophagy; Autophagy - genetics; Autophagy-Related Protein 5 - genetics; Body mass index; Cytotoxicity; DNA methylation; DNA Methylation - genetics; Electroencephalography; Epigenesis, Genetic; Epigenetic inheritance; Gene expression; Genes; Homeostasis; Humans; Hypertension; Hypoxia; Intermittent hypoxia with re-oxygenation; Ischemia; Kinases; Leukocytes, Mononuclear; Lymphocytes; Medical law; Mesenchymal stem cell; Methylation; Neutrophils; Obstructive sleep apnea; Oxidative stress; Oxidative Stress - genetics; Proteins; Rapamycin; Sleep apnea; Sleep apnea syndromes; Stem cells; T cells
• ISSN: 2047-783X; 0949-2321; 2047-783X
• DOI: 10.1186/s40001-023-01051-4

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). 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). 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. 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.