Abstract
Obstructive sleep apnea (OSA) is a common breathing disorder affecting a significant percentage of the adult population. OSA is an independent risk factor for cardiovascular disease (CVD); however, the underlying mechanisms are not completely understood. Since the severity of hypoxia correlates with some of the cardiovascular effects, intermittent hypoxia (IH) is thought to be one of the mechanisms by which OSA may cause CVD. Here, we investigated the effect of IH on endothelial cell (EC) activation, characterized by the expression of inflammatory genes, that is known to play an important role in the pathogenesis of CVD. Exposure of C57BL/6 mice to IH led to aortic EC activation, while in vitro exposure of ECs to IH failed to do so, suggesting that IH does not induce EC activation directly, but indirectly. One of the consequences of IH is activation of the sympathetic nervous system and catecholamine release. We found that exposure of mice to IH caused elevation of circulating levels of catecholamines. Inhibition of the IH-induced increase in catecholamines by pharmacologic inhibition or by adrenalectomy or carotid body ablation prevented the IH-induced EC activation in mice. Supporting a key role for catecholamines, epinephrine alone was sufficient to cause EC activation in vivo and in vitro. Together, these results suggested that IH does not directly induce EC activation, but does so indirectly via release of catecholamines. These results suggest that targeting IH-induced sympathetic nerve activity and catecholamine release may be a potential therapeutic target to attenuate the CV effects of OSA.
Highlights
Obstructive sleep apnea (OSA) is a common breathing disorder affecting a significant percentage of the adult population
Intermittent Hypoxia For in vivo exposure to intermittent hypoxia (IH), mice were placed in a specialized chamber, which is flushed with cycles of pure nitrogen and compressed air following a chronic IH protocol consisting of 15 s of 5% O2 followed by 5 min of 21% O2, 9 episodes/h and 8 h per day for 10 days as previously described (Peng et al, 2006)
Intermittent Hypoxia Induces Aortic endothelial cell (EC) Activation in vivo but Not in vitro Given that EC activation plays an important role in the pathogenesis of cardiovascular disease (CVD), we first sought to determine whether IH causes EC activation as a mechanism to explain the increased prevalence of CVD in OSA
Summary
Obstructive sleep apnea (OSA) is a common breathing disorder affecting a significant percentage of the adult population. The frequency of CVD increases with the severity of OSA (Marin et al, 2005), and some of the cardiovascular effects of OSA, such as hypertension, show linear correlation with the severity of hypoxia (McNicholas et al, 2007). Patients with OSA exhibit increased sympathetic nerve activity (Dempsey et al, 2010; Prabhakar, 2016) as well as elevated circulating and urinary catecholamines (both norepinephrine and epinephrine), which are attributed to heightened sympathetic nerve activity (Fletcher et al, 1987; Carlson et al, 1993; Marrone et al, 1993; Somers et al, 1995; Peng et al, 2021). The specific roles that IH and heightened sympathetic nerve activity play in the pathogenesis of cardiovascular morbidity seen in OSA are not completely understood.
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