PMID- 23328524
OWN - NLM
STAT- MEDLINE
DCOM- 20130927
LR  - 20220408
IS  - 1535-4970 (Electronic)
IS  - 1073-449X (Print)
IS  - 1073-449X (Linking)
VI  - 188
IP  - 2
DP  - 2013 Jul 15
TI  - Chronic intermittent hypoxia induces atherosclerosis via activation of adipose 
      angiopoietin-like 4.
PG  - 240-8
LID - 10.1164/rccm.201209-1688OC [doi]
AB  - RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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-1alpha knockout allele. Transgenic 
      overexpression of HIF-1alpha in adipose tissue led to dyslipidemia and increased 
      levels of adipose Angptl4. In cultured adipocytes, constitutive expression of 
      HIF-1alpha 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.
FAU - Drager, Luciano F
AU  - Drager LF
AD  - Division of Pulmonary and Critical Care Medicine, Institute for Cell Engineering, 
      Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
FAU - Yao, Qiaoling
AU  - Yao Q
FAU - Hernandez, Karen L
AU  - Hernandez KL
FAU - Shin, Mi-Kyung
AU  - Shin MK
FAU - Bevans-Fonti, Shannon
AU  - Bevans-Fonti S
FAU - Gay, Jason
AU  - Gay J
FAU - Sussan, Thomas E
AU  - Sussan TE
FAU - Jun, Jonathan C
AU  - Jun JC
FAU - Myers, Allen C
AU  - Myers AC
FAU - Olivecrona, Gunilla
AU  - Olivecrona G
FAU - Schwartz, Alan R
AU  - Schwartz AR
FAU - Halberg, Nils
AU  - Halberg N
FAU - Scherer, Philipp E
AU  - Scherer PE
FAU - Semenza, Gregg L
AU  - Semenza GL
FAU - Powell, David R
AU  - Powell DR
FAU - Polotsky, Vsevolod Y
AU  - Polotsky VY
LA  - eng
GR  - M01 RR002719/RR/NCRR NIH HHS/United States
GR  - M01-RR02719/RR/NCRR NIH HHS/United States
GR  - P30 DK079637/DK/NIDDK NIH HHS/United States
GR  - HL084945/HL/NHLBI NIH HHS/United States
GR  - P50 HL084945/HL/NHLBI NIH HHS/United States
GR  - HL080105/HL/NHLBI NIH HHS/United States
GR  - K08 HL109475/HL/NHLBI NIH HHS/United States
GR  - HL109475/HL/NHLBI NIH HHS/United States
GR  - R01 HL080105/HL/NHLBI NIH HHS/United States
GR  - P30 DK072488/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Respir Crit Care Med
JT  - American journal of respiratory and critical care medicine
JID - 9421642
RN  - 0 (Angiopoietin-Like Protein 4)
RN  - 0 (Angiopoietins)
RN  - 0 (Angptl4 protein, mouse)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 3.1.1.34 (Lipoprotein Lipase)
SB  - IM
MH  - Adipocytes/metabolism
MH  - Adult
MH  - Aged
MH  - Angiopoietin-Like Protein 4
MH  - Angiopoietins/*metabolism
MH  - Animals
MH  - Apolipoproteins E/deficiency
MH  - Atherosclerosis/metabolism/*physiopathology
MH  - Female
MH  - Humans
MH  - Hypoxia/metabolism/*physiopathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Lipoprotein Lipase/antagonists & inhibitors
MH  - Mice
MH  - Mice, Inbred SENCAR
MH  - Middle Aged
MH  - Obesity/metabolism/physiopathology
MH  - Sleep Apnea, Obstructive/metabolism/*physiopathology
MH  - Subcutaneous Fat/metabolism/*physiopathology
MH  - Up-Regulation/physiology
PMC - PMC3778753
EDAT- 2013/01/19 06:00
MHDA- 2013/09/28 06:00
PMCR- 2014/07/15
CRDT- 2013/01/19 06:00
PHST- 2013/01/19 06:00 [entrez]
PHST- 2013/01/19 06:00 [pubmed]
PHST- 2013/09/28 06:00 [medline]
PHST- 2014/07/15 00:00 [pmc-release]
AID - rccm.201209-1688OC [pii]
AID - 10.1164/rccm.201209-1688OC [doi]
PST - ppublish
SO  - Am J Respir Crit Care Med. 2013 Jul 15;188(2):240-8. doi: 
      10.1164/rccm.201209-1688OC.