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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 V_ 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.

Original languageEnglish
Pages (from-to)323-335
Number of pages13
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume207
Issue number3
DOIs
StatePublished - 1 Feb 2023

Keywords

  • endothelium
  • miR-210
  • mitochondrial dysfunction
  • obstructive sleep apnea

Fingerprint

Dive into the research topics of 'Obstructive Sleep Apnea–induced Endothelial Dysfunction Is Mediated by miR-210'. Together they form a unique fingerprint.

Cite this