Endothelial nitric oxide synthase uncoupling: A novel pathway in OSA induced vascular endothelial dysfunction

Abstract

The mechanism of vascular endothelial dysfunction (VED) and cardiovascular disease in obstructive sleep apnea (OSA) is unknown. We performed a comprehensive evaluation of endothelial nitric oxide synthase (eNOS) function directly in the microcirculatory endothelial tissue of OSA patients who have very low cardiovascular risk status. Nineteen OSA patients underwent gluteal biopsies before, and after effective treatment of OSA. We measured superoxide (O2−·) and nitric oxide (NO) in the microcirculatory endothelium using confocal microscopy. We evaluated the effect of the NOS inhibitor L-Nitroarginine-Methyl-Ester (L-NAME) and the NOS cofactor tetrahydrobiopterin (BH4) on endothelial O2−· and NO in patient endothelial tissue before and after treatment. We found that eNOS is dysfunctional in OSA patients pre-treatment, and is a source of endothelial O2−· overproduction. eNOS dysfunction was reversible with the addition of BH4. These findings provide a new mechanism of endothelial dysfunction in OSA patients and a potentially targetable pathway for treatment of cardiovascular risk in OSA.

Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia

“…Oxidative stress can increase ADMA levels by oxidizing and deactivating the enzyme responsible for ADMA elimination (dimethylarginine dimethylaminohydrolase (DDAH)) [43]. Our findings reveal that ADMA levels are increased by CIH and diabetes, with ADMA levels being greater in db/db mice exposed to CIH.…”

“…Tetrahydrobiopterin (BH 4 ) is a cofactor essential for NO production; oxidative stress leads to its oxidation and eNOS uncoupling [42]. Supplementation with BH 4 reverses endothelial dysfunction in OSA patients [43]. We evaluated eNOS uncoupling in the endothelial layer of aortic sections by measuring the fluorescence of the superoxide-sensitive dye (DHE) with or without incubation with L-NAME (eNOS inhibitor).…”

Oxidative Stress and Hypertensive Diseases

“…22 There is also convincing evidence that eNOS uncoupling occurs in humans with obstructive sleep apnea, leading to increased vascular superoxide production and endothelial dysfunction. 23 Thus, reversing NOS uncoupling is an attractive approach to improve endothelium function and prevent the pathogenesis of vascular diseases.…”

The Ventilatory and Diffusion Dysfunctions in Obese Patients with and without Obstructive Sleep Apnea-Hypopnea Syndrome

“…e comparison between OSAS and control groups showed a significant lower FEV 1 (L and %) in the OSAS group. is could be explained by the rise in oxidative stress during OSAS leading to a decrease in NO synthesis by pulmonary tissue and causing bronchial muscles relaxation defect [34,37,38]. However, FEV 1 was considered by several authors to be an unsuitable tool for assessing the functional impact of OSAS since these data did not show a significant difference between participants with and without OSAS during their studies [11,28,39].…”