학술논문
Obstructive Sleep Apnea-induced Endothelial Dysfunction Is Mediated by miR-210.
Document Type
article
Author
Shang, Fenqing; Wang, Shen-Chih; Gongol, Brendoan; Han, So Yun; Cho, Yoshitake; Schiavon, Cara R; Chen, Lili; Xing, Yuanming; Zhao, Yingshuai; Ning, Ming'an; Guo, Xuan; He, Fangzhou; Lei, Yuyang; Wang, Liuyi; Manor, Uri; Marin, Traci; Chou, Kun-Ta; He, Ming; Huang, Po-Hsun; Shyy, John Y-J; Malhotra, Atul
Source
American Journal of Respiratory and Critical Care Medicine. 207(3)
Subject
Language
Abstract
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.