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.
Highlights
Obstructive sleep apnea (OSA) is a common sleep disorder that associated with high prevalence of 15% in men and 5% in women [1]
We further examined expression of apoptosis-related proteins, such as apoptosis-inducing factor (AIF), Caspase 3, B cell lymphoma/lewkmia-2 (Bcl-2) and Bcl-2 Associated X Protein (Bax) and found that chronic OSA increased protein levels of AIF, Caspase 3 and Bax, while decreased protein level of Bcl-2 compared with sham group (P < 0.05, Figure 4B, 4C)
We demonstrated that chronic OSA could cause aortic structural and autonomic nerve remodeling by promoting aortic fibrosis, apoptosis and sympathetic nerve sprouting and innervating in a canine model
Summary
Obstructive sleep apnea (OSA) is a common sleep disorder that associated with high prevalence of 15% in men and 5% in women (aged 30-70 years) [1]. Kohler et al [11] demonstrated a considerably higher prevalence of OSA in Marfan’s syndrome patients, OSA promoted aortic dilatation and associated aortic dissection in patients with Marfan’s syndrome. Despite these clinical findings, the concrete effects and mechanisms of chronic OSA in aortic diseases have not yet been clearly confirmed, mainly owing to many closely related confounders (e.g. age, sex, obesity, hypertension, etc.). The present study aimed to clarify the pathologic changes of aortic structures and elucidate the underlying mechanism in a chronic OSA canine model
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