NADPH oxidase, uncoupled endothelial nitric oxide synthase, and NF-KappaB are key mediators of the pathogenic impact of obstructive sleep apnea – Therapeutic implications

Obstructive sleep apnea (OSA) markedly increases risk for atherosclerosis, systemic and pulmonary hypertension, ventricular hypertrophy, myocardial infarction, stroke, and sudden-death arrhythmias; it also has adverse psychological effects, including daytime somnolence.Clinical and rodent studies indicate that oxidative stress and inflammation underlie the pathogenesis of these complications.NADPH oxidase complexes have emerged as a key source of this oxidative stress, which is amplified in vascular endothelium by uncoupled nitric oxide synthase (eNOS).Proteolytic conversion of xanthine dehydrogenase to xanthine oxidase triggered by hypoxia appears to be upstream from NADPH oxidase activation during intermittent hypoxia.Activation of NF-kappaB downstream from this oxidative stress promotes the inflammation associated with OSA.These considerations suggest therapeutic avenues that, when OSA cannot be fully controlled with CPAP, may lessen the pathogenic impact of this syndrome.The elevated NADPH oxidase activity in OSA might be addressed with spirulina, whose chromophore phycocyanobilin can potently inhibit NADPH oxidases in a manner analogous to bilirubin.Xanthine oxidase inhibitor allopurinol may suppress NADPH oxidase activation in OSA, and has been shown to improve endothelial function in OSA patients.The adverse impact of oxidative stress might be antagonized to some extent by administration of N-acetylcysteine, a glutathione precursor.The uncoupling of eNOS -both a cause and a consequence of oxidative stress -could be combatted with supplemental citrulline and high-dose folate.Docosahexaenoic acid could be of potential benefit by promoting expression of phase 2 antioxidant enzymes.In patients who tolerate it adequately, moderate-dose salsalate could be employed to down-regulate canonical NF-kappaB activation.Considerable evidence points to NADPH oxidase complexes as a key source of the oxidative stress underlying OSA, and to increased activation of NF-kappaB as a mediator of the associated inflammation.Additionally, in vascular endothelium, uncoupling of the endothelial nitric oxide synthase (eNOS) contributes both to oxidative stress and a loss of protective NO bioactivity.40,