TY - JOUR
T1 - Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4
AU - Drager, Luciano F.
AU - Yao, Qiaoling
AU - Hernandez, Karen L.
AU - Shin, Mi Kyung
AU - Bevans-Fonti, Shannon
AU - Gay, Jason
AU - Sussan, Thomas E.
AU - Jun, Jonathan C.
AU - Myers, Allen C.
AU - Olivecrona, Gunilla
AU - Schwartz, Alan R.
AU - Halberg, Nils
AU - Scherer, Philipp E.
AU - Semenza, Gregg L.
AU - Powell, David R.
AU - Polotsky, Vsevolod Y.
PY - 2013/7/15
Y1 - 2013/7/15
N2 - 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. Hypoxiainduced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1a knockout allele. Transgenic overexpression of HIF-1a in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1a increasedAngptl4 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 inactivationmaycontribute to atherosclerosis in patients with sleep apnea.
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. Hypoxiainduced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1a knockout allele. Transgenic overexpression of HIF-1a in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1a increasedAngptl4 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 inactivationmaycontribute to atherosclerosis in patients with sleep apnea.
KW - Adipose tissue
KW - Hypoxia-inducible factor-1
KW - Lipoprotein clearance
KW - Lipoprotein lipase
KW - Sleep apnea
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U2 - 10.1164/rccm.201209-1688OC
DO - 10.1164/rccm.201209-1688OC
M3 - Article
C2 - 23328524
AN - SCOPUS:84875844834
SN - 1073-449X
VL - 188
SP - 240
EP - 248
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 2
ER -