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

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.

Association between peripheral blood cells mitochondrial DNA content and severity of coronary heart disease.

BACKGROUND AND AIMS: Leukocyte mitochondrial DNA (mtDNA) content reflects the oxidant-induced cell damage, which has been observed in a wide range of cardiovascular diseases. However, whether it correlates with coronary heart disease (CHD), which closely relates to oxidative stress, has never been elucidated before. The aim of this study was to explore association between mtDNA content and the presence and severity of CHD. METHODS: The study population consisted of 400 individuals (290 with CHD and 110 controls). A quantitative real-time PCR was performed to measure the relative content of mtDNA in peripheral blood cells (PBCs). Gensini score was used to evaluate the severity of coronary stenotic lesions. An unconditional multivariate logistic regression was developed to estimate the association between CHD risk and mtDNA content by using odds ratio (OR). This study is registered with ClinicalTrials.gov, number NCT02500823. RESULTS: CHD patients, compared to controls, had lower mtDNA content (median, 0.78 vs. 0.83, p < 0.001), and mtDNA levels significantly decreased following an increasing Gensini score (p < 0.001). By using the first (highest mtDNA content) quartile of mtDNA content of controls as reference, the adjusted ORs (95% CIs) for individuals in the second, third and highest quartile of mtDNA content were 1.78 (95% CI, 1.15-3.51), 2.21 (95% CI, 1.65-3.74) and 4.83 (95% CI, 2.67-8.64), respectively (p for trend <0.001). CONCLUSIONS: These preliminary results suggest that expression of mtDNA may be associated with atherogenesis. The level of peripheral blood mtDNA in predicting the severity of coronary atherosclerosis may have a relatively certain value.