Obstructive Sleep Apnea-induced Endothelial Dysfunction Is Mediated by miR-210.

American journal of respiratory and critical care medicine 2023 Feb 01

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Rationale: Obstructive sleep apnea (OSA)-induced endothelial cell (EC) dysfunction contributes to OSA-related cardiovascular sequelae. The mechanistic basis of endothelial impairment by OSA is unclear. Objectives: The goals of this study were to identify the mechanism of OSA-induced EC dysfunction and explore the potential therapies for OSA-accelerated cardiovascular disease. Methods: The experimental methods include data mining, bioinformatics, EC functional analyses, OSA mouse models, and assessment of OSA human subjects. Measurements and Main Results: Using mined microRNA sequencing data, we found that microRNA 210 (miR-210) conferred the greatest induction by intermittent hypoxia in ECs. Consistently, the serum concentration of miR-210 was higher in individuals with OSA from two independent cohorts. Importantly, miR-210 concentration was positively correlated with the apnea-hypopnea index. RNA sequencing data collected from ECs transfected with miR-210 or treated with OSA serum showed a set of genes commonly altered by miR-210 and OSA serum, which are largely involved in mitochondrion-related pathways. ECs transfected with miR-210 or treated with OSA serum showed reduced [Formula: see text]o2 rate, mitochondrial membrane potential, and DNA abundance. Mechanistically, intermittent hypoxia-induced SREBP2 (sterol regulatory element-binding protein 2) bound to the promoter region of miR-210, which in turn inhibited the iron-sulfur cluster assembly enzyme and led to mitochondrial dysfunction. Moreover, the SREBP2 inhibitor betulin alleviated intermittent hypoxia-increased systolic blood pressure in the OSA mouse model. Conclusions: These results identify an axis involving SREBP2, miR-210, and mitochondrial dysfunction, representing a new mechanistic link between OSA and EC dysfunction that may have important implications for treating and preventing OSA-related cardiovascular sequelae.

Citation

Fenqing Shang, Shen-Chih Wang, Brendoan Gongol, So Yun Han, Yoshitake Cho, Cara R Schiavon, Lili Chen, Yuanming Xing, Yingshuai Zhao, Ming'an Ning, Xuan Guo, Fangzhou He, Yuyang Lei, Liuyi Wang, Uri Manor, Traci Marin, Kun-Ta Chou, Ming He, Po-Hsun Huang, John Y-J Shyy, Atul Malhotra. Obstructive Sleep Apnea-induced Endothelial Dysfunction Is Mediated by miR-210. American journal of respiratory and critical care medicine. 2023 Feb 01;207(3):323-335