Breaking barriers in obstructive sleep apnea. Focus on “Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation”

Abstract

ONE OF THE MORE COMMON HEALTH issues affecting our society is obstructive sleep apnea (OSA), which affects at least 10% of the general population, primarily overweight or obese men (12). OSA, defined as the cessation of breathing caused by the repetitive, episodic collapse of the pharyngeal airway due to an airway obstruction or increased airway resistance during sleep, is a well-known public health problem due to its prevalence and the severe consequences of this disorder. The most common symptoms of OSA are morning fatigue, increased daytime sleepiness, arousals with nocturnal diuresis, and frequent snoring, yet many patients present with minimal or absent symptoms by compensating with lifestyle modifications. OSA is diagnosed following a sleep evaluation with polysomnography, which involves simultaneous recording of sleep, air flow, respiratory effort, oxygen saturation, and brain activity. The consequences of OSA include neurocognitive impairment and cardiovascular morbidities including hypertension, stroke, coronary artery disease, and heart failure (7). Additionally, several studies have shown OSA to be associated with pulmonary edema (4) and pulmonary hypertension (10). A substantial number of patients with cardiac disorders and concomitant OSA do not report excessive daytime sleepiness and are therefore not considered for diagnostic sleep evaluation and treatment for OSA. It is well understood that untreated OSA can lead to the progression of cardiovascular disease and increased mortality. Recurrent apneas result in chronic intermittent hypoxia (CIH), a hallmark of OSA. Exposure of rats and mice to CIH for 3 to 5 weeks is sufficient to induce pathological changes similar to those seen in OSA patients, such as endothelial dysfunction, atherosclerosis, systemic hypertension, pulmonary hypertension, and heart failure (3). It has been suggested that the carotid bodies constitute the frontline defense system for detecting systemic hypoxia associated with apneas (2). The two major effects exerted by CIH on the carotid body are augmented response to acute hypoxia and long-lasting activation of the carotid body, which persist for several hours after termination of CIH (9). It has been proposed that the pathological effects of CIH-induced augmented carotid body responses are due to increased reactive oxygen species (ROS) (8). CIH results in increased ROS by both upregulation of pro-oxidants and downregulation of anti-oxidants (6). ROS are a group of highly unstable molecules generated during normal cellular metabolism or during incomplete reduction of molecular oxygen. These species are involved in the regulation of fundamental cellular activities such as growth and differentiation, however, overproduction of ROS results in oxidative stress and causes significant injury (11). Mice and rats exposed to CIH display elevated ROS in the carotid body, adrenal medulla, and central nervous system resulting in increased