title: Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4.
abstract: BACKGROUND
  Obstructive sleep apnea is a risk factor for dyslipidemia and atherosclerosis, which have been attributed to chronic intermittent hypoxia (CIH). Intermittent hypoxia inhibits a key enzyme of lipoprotein clearance, lipoprotein lipase, and up-regulates a lipoprotein lipase inhibitor, angiopoietin-like 4 (Angptl4), in adipose tissue. The effects and mechanisms of Angptl4 up-regulation in sleep apnea are unknown.
  
  
  OBJECTIVE
  To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1).
  
  
  METHODS
  ApoE(-/-) mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle.
  
  
  RESULTS
  In vehicle-treated mice, hypoxia increased adipose Angptl4 levels, inhibited adipose lipoprotein lipase, increased fasting levels of plasma triglycerides and very low density lipoprotein cholesterol, and increased the size of atherosclerotic plaques. The effects of CIH were abolished by the antibody. Hypoxia-induced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1α knockout allele. Transgenic overexpression of HIF-1α in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1α increased Angptl4 levels, which was abolished by siRNA. Finally, in obese patients undergoing bariatric surgery, the severity of nocturnal hypoxemia predicted Angptl4 levels in subcutaneous adipose tissue.
  
  
  CONCLUSIONS
  HIF-1-mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase inactivation may contribute to atherosclerosis in patients with sleep apnea.
authors: Division of Pulmonary and Critical Care Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors: Luciano F
authors: LF
authors: Drager
authors: Qiaoling
authors: Q
authors: Yao
authors: Karen L
authors: KL
authors: Hernandez
authors: Mi-Kyung
authors: MK
authors: Shin
authors: Shannon
authors: S
authors: Bevans-Fonti
authors: Jason
authors: J
authors: Gay
authors: Thomas E
authors: TE
authors: Sussan
authors: Jonathan C
authors: JC
authors: Jun
authors: Allen C
authors: AC
authors: Myers
authors: Gunilla
authors: G
authors: Olivecrona
authors: Alan R
authors: AR
authors: Schwartz
authors: Nils
authors: N
authors: Halberg
authors: Philipp E
authors: PE
authors: Scherer
authors: Gregg L
authors: GL
authors: Semenza
authors: David R
authors: DR
authors: Powell
authors: Vsevolod Y
authors: VY
authors: Polotsky
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000328:Adult; D000368:Aged; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D051379:Mice; D018632:Mice, Inbred SENCAR; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D020181:Sleep Apnea, Obstructive / Q000378:metabolism / Q000503:physiopathology*; D050151:Subcutaneous Fat / Q000378:metabolism / Q000503:physiopathology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D001057:Apolipoproteins E; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008071:Lipoprotein Lipase