Abstract
// Kai-Xiong Liu 1, 2, 3 , Qin Chen 4 , Gong-Ping Chen 1, 2, 3 , Jian-Chai Huang 1, 2, 3 , Jie-Feng Huang 1, 2, 3 , Xin-Ru He 1, 2, 3 , Ting Lin 1, 2, 3 and Qi-Chang Lin 1, 2, 3 1 Department of Respiratory Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China 2 Laboratory of Respiratory Disease of Fujian Medical University, Fuzhou 350005, China 3 Fujian Provincial Sleep-Disordered Breathing Clinic Center, Fuzhou 350005, China 4 Integrated Chinese and Western Medicine Colleges, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China Correspondence to: Qi-Chang Lin, email: chang4e@126.com Keywords: chronic intermittent hypoxia (CIH); obstructive sleep apnea (OSA); autophagy; Beclin-1; miR-30a Received: August 21, 2017 Accepted: September 03, 2017 Published: January 02, 2018 ABSTRACT Chronic intermittent hypoxia (CIH) in obstructive sleep apnea causes damages of aortic endothelial cells, which predisposes development of many cardiovascular diseases. Recently, both altered expression of microRNAs (miRNAs) and impaired autophagy were found to be associated with endothelial cell dysfunction in CIH. However, the exact molecular regulatory pathway has not been determined. Here, we addressed this question. In a mouse model of CIH, we detected significant upregulation of miR-30a, a miRNA that targets 3′-UTR of autophagy-associated protein 6 (Beclin-1) mRNA to suppress the protein translation, which subsequently attenuated the endothelial cell autophagy against cell death. Indeed, unlike Beclin-1 mRNA, the Beclin-1 protein in endothelial cells did not increase after CIH. Suppression of miR-30a by expression of antisense of miR-30a significantly increased Beclin-1 levels to enhance endothelial cell autophagy in vitro and in vivo , which improved endothelial cell survival against CIH. Together, these data suggest that endothelial cell autophagy in CIH may be attenuated by miR-30a-mediated translational control of Beclin-1, as an important cause of endothelial cell dysfunction and damage.
Highlights
Obstructive sleep apnea (OSA) is a prevalent sleep disorder that causes repetitive collapse of the upper airway, asphyxia, oxygen desaturation and chronic intermittent hypoxia (CIH) [1]
After 8 weeks, we found that the Chronic intermittent hypoxia (CIH) mice exhibited echocardiographic defects, including significantly increased end-diastolic volume (EDV, Figure 1A), significantly increased endsystolic volume (ESV, Figure 1B), significantly reduced percentage of ejection fraction (EF%, Figure 1C), and significantly reduced percentage of fractional shortening (FS%, Figure 1D), compared to the control mice (CTL)
A previous study has shown the role of miRNAs in CIH as well as the relationship between endothelial cell apoptosis and endothelial dysfunction [23], but the molecular mechanisms remain undetermined
Summary
Obstructive sleep apnea (OSA) is a prevalent sleep disorder that causes repetitive collapse of the upper airway, asphyxia, oxygen desaturation and chronic intermittent hypoxia (CIH) [1]. OSA is an independent risk for cardiovascular diseases, e.g. systemic arterial hypertension, ischemic heart disease, cardiac arrhythmias, metabolic disorders, and cognitive dysfunction, likely owing to its associated CIH and re-oxygenation processes [2]. The pathogenesis of OSA-induced cardiovascular diseases has been found to involve endothelial dysfunction secondary to oxidative stress and activation of inflammation [3]. The most important feature of endothelial dysfunctions are endothelial cell damage and impaired stimulated vasodilatation, as a precursor of atherosclerosis in human [2]. The failure or inhibition of autophagy results in augmentation of endothelial cell apoptosis, leading to the break-down of the integrity of endothelium to facilitate endothelial dysfunction [5]. Cytoplasmic constituents are sequestered and targeted for lysosomal degradation and re-cycling by autophagosomes, in which a cytosolic form of microtubule-associated www.impactjournals.com/oncotarget s253
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