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

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.

Upper Airway Stimulation vs Positive Airway Pressure Impact on BP and Sleepiness Symptoms in OSA

“…One should also emphasize that the patients with UAS were PAP intolerant and may have had exposure to untreated OSA pathophysiology for a longer period of time (despite the matching), with possible irreversibility of vascular dysfunction, thereby mitigating appreciation of BP benefit potentially due to vascular remodeling. 30 In our study, the posttherapy reduction in ESS with UAS was 3.7 points compared with a 2.7-point reduction with PAP, despite similar baseline ESS score. This degree of reduction is somewhat congruent with existing literature, which describes an average 5-year reduction in ESS of 4.4 points in patients with UAS implantation.…”

MiRNA expression profiles in healthy OSAHS and OSAHS with arterial hypertension: potential diagnostic and early warning markers

“…A recent study exhibited that miR-145 was significantly suppressed and Smad3 was subsequently increased in hypoxia-treated VSMCs. Moreover, miR-145/Smad3 signaling pathway might promote OSAHS-induced aortic remodeling, which might be initiated by inflammation and oxidative stress [ 62 ]. In addition, hypoxia was found to aggravate inflammatory response and miR-145-5p might play an anti-inflammatory role to protect cells from ischemic and hypoxic injury [ 63 ].…”

MicroRNA expression profile during different conditions of hypoxia

“…Up-regulating the expression of miR-23 may help to protect cells from injury-induced apoptotic cell death enabling contribution to cell proliferation [ 18 ]. MiRNA-145 has an important role in many inflammatory processes involved in Asthma as well as in COPD [ 19 ] but additionally seems to be a promoter of OSA mechanisms such as aortic fibrosis, apoptosis and sympathetic nerve sprouting in a canine model [ 20 ]. Our results confirm that intermittent hypoxia, more than chronic hypoxia, increases the level of miR-145 also in human subjects, and this could be a reason why in cardiovascular diseases are more frequent in patients with OSA.…”