Oncotarget

Research Papers:

Chronic obstructive sleep apnea promotes aortic remodeling in canines through miR-145/Smad3 signaling pathway

Chengyuan Yu, Yang Liu, Li Sun, Dingyu Wang, Yike Wang, Shiqi Zhao, Hui Dai, Jing Zhao, Song Zhang, Minghui Li, Yu Han, Shuang Lu, Xinwen Dong, Guangzhong Liu, Shengzhu Yu and Yue Li _

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Oncotarget. 2017; 8:37705-37716. https://doi.org/10.18632/oncotarget.17144

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Abstract

Chengyuan Yu1,*, Yang Liu1,*, Li Sun1,*, Dingyu Wang1, Yike Wang1, Shiqi Zhao1, Hui Dai1, Jing Zhao2, Song Zhang1, Minghui Li1, Yu Han1, Shuang Lu1, Xinwen Dong1, Guangzhong Liu1, Shengzhu Yu4 and Yue Li1,2,3

1Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150001, Heilongjiang Province, P. R. China

2Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin, 150001, Heilongjiang Province, P. R. China

3Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, 150086, Heilongjiang Province, P. R. China

4College of Resources and Environment, Northeast Agricultural University, Harbin, 150030, Heilongjiang Province, P. R. China

*These authors have contributed equally to this work

Correspondence to:

Yue Li, email: [email protected]

Keywords: obstructive sleep apnea, canine, aortic remodeling, miR-145, Smad3

Received: May 14, 2016     Accepted: March 28, 2017     Published: April 17, 2017

ABSTRACT

Obstructive sleep apnea (OSA) is a causal pathogenetic factor of many cardiovascular diseases, however, its role in aortic diseases remains unknown. Therefore, this study was performed to explore the potential effects and pathophysiological mechanisms of chronic OSA on aortic remodeling in a canine model. After chronic OSA, the morphological changes of ascending aorta were characterized by thinner cells with pycnotic nuclei and swollen mitochondria, and obvious hyperplasia of collagenous fiber in the matrix. Both the apoptotic ratio and collagen volume fraction were significantly increased in ascending aorta of chronic OSA canines. Besides, aortic sympathetic nerve sprouting increased significantly in chronic OSA group. Meanwhile, protein expression of TGF-β1, Smad3, collagenI, apoptosis-inducing factor (AIF), tyrosine hydroxylase (TH) and growth associated protein-43 (GAP43) was upregulated after chronic OSA. Additionally, chronic OSA also strikingly increased pro-inflammatory factors like tumor necrosis factor α (TNF-α), NOD-like receptor 3 (NLRP3), NF-κB-p65 and oxidative stress factors like xanthine oxidase (XOD), malondialdehyde (MDA) while declined superoxide dismutase (SOD) activity. Furthermore, suppressed miR-145 and subsequently increased Smad3 expression were found obviously in vascular smooth muscle cells (VSMCs) treated by hypoxia. Luciferase reporter assays confirmed that Smad3 was one of the targets of miR-145. In conclusion, OSA could exacerbate aortic remodeling by aortic fibrosis, apoptosis and sympathetic nerve sprouting. miR-145/Smad3 signaling pathway might promote aortic remodeling during OSA. These findings provide novel information of chronic OSA-induced vascular dysfunction.


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