Chronic intermittent hypoxia down-regulates endothelial nitric oxide synthase expression by an NF-κB-dependent mechanism

Abstract

Patients with obstructive sleep apnea have an impaired endothelium-dependent vasodilator response. The mechanisms underlying this impairment remain unclear. We tested the hypothesis that chronic intermittent hypoxia (CIH) impairs endothelium-dependent vasodilatation by NF-κB-mediated down-regulation of endothelial nitric oxide synthase (eNOS) expression. Wild type (WT) mice and mice deficient in NF-κB p50 or TNF-α gene were exposed to sham or CIH. Aortic NF-κB activity and aortic expression of TNF-α were determined. Aortic and mesenteric artery levels of eNOS expression were examined and their correlation to endothelium-dependent vasodilator response in vitro and vasodepressor response in vivo were analyzed. WT mice exposed to CIH for five to eight weeks showed significantly reduced eNOS protein expression in aortas and mesenteric arteries, associated with significantly blunted vasodilator and vasodepressor responses to acetylcholine, but not to sodium nitroprusside. CIH activated NF-κB, which preceded TNF-α up-regulation and eNOS down-regulation. NF-κB p50 gene deletion blocked NF-κB activation, inhibited TNF-α expression, prevented eNOS down-regulation and reversed the impaired endothelium-dependent vasodepressor response induced by CIH. TNF-α knockout prevented CIH-induced eNOS down-regulation and restored the endothelium-dependent vasodepressor response. CIH exposure impairs endothelium-dependent vasodilator mechanism by stimulating NF-κB-mediated TNF-α generation, which in turn, down-regulates eNOS expression, resulting in an impaired endothelium-dependent vasodilatation.