title: Chronic intermittent hypoxia down-regulates endothelial nitric oxide synthase expression by an NF-κB-dependent mechanism.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, China. baoshanwang95@126.com
authors.forename: Baoshan
authors.initials: B
authors.lastname: Wang
authors.forename: Baoyong
authors.initials: B
authors.lastname: Yan
authors.forename: Dongmei
authors.initials: D
authors.lastname: Song
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Ye
authors.forename: Shu Fang
authors.initials: SF
authors.lastname: Liu
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D020181:Sleep Apnea, Obstructive / Q000235:genetics / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D009599:Nitroprusside; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine