Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4

• Published in: American journal of respiratory and critical care medicine Vol. 188; no. 2; pp. 240 - 248
• Main Authors: DRAGER, Luciano F, QIAOLING YAO, SCHWARTZ, Alan R, HALBERG, Nils, SCHERER, Philipp E, SEMENZA, Gregg L, POWELL, David R, POLOTSKY, Vsevolod Y, HERNANDEZ, Karen L, SHIN, Mi-Kyung, BEVANS-FONTI, Shannon, GAY, Jason, SUSSAN, Thomas E, JUN, Jonathan C, MYERS, Allen C, OLIVECRONA, Gunilla
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 15.07.2013
• Subjects: Adipocytes - metabolism; adipose tissue; Adult; Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Angiopoietin-like 4 Protein; Angiopoietins - metabolism; Animals; Antibodies; Apolipoproteins E - deficiency; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - metabolism; Atherosclerosis - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Body fat; Cardiology. Vascular system; Cholesterol; Enzymes; Female; Gastrointestinal surgery; Humans; Hypotheses; Hypoxia; Hypoxia - metabolism; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia-inducible factor-1; Intensive care medicine; lipoprotein clearance; lipoprotein lipase; Lipoprotein Lipase - antagonists & inhibitors; Lipoproteins; Medical sciences; Metabolic disorders; Mice; Mice, Inbred SENCAR; Middle Aged; Obesity - metabolism; Obesity - physiopathology; Plasma; Pneumology; Respiratory system : syndromes and miscellaneous diseases; Sleep apnea; Sleep Apnea, Obstructive - metabolism; Sleep Apnea, Obstructive - physiopathology; Statistical significance; Subcutaneous Fat - metabolism; Subcutaneous Fat - physiopathology; Triglycerides; Up-Regulation - physiology; Intensive care; Adipose tissue; Cardiovascular disease; Esterases; Activation; Lipoprotein lipase; Clearance; Lipoprotein; Vascular disease; Intermittent; Atherosclerosis; sleep apnea; Resuscitation; lipoprotein clearance; Nervous system diseases; Oxygen; Sleep apnea syndrome; Enzyme; Respiratory disease; Carboxylic ester hydrolases; Chronic; hypoxia-inducible factor-1; Hydrolases; Hypoxia; Transcription factor HIF1
• DOI: 10.1164/rccm.201209-1688oc
• ISSN: 1073-449X; 1535-4970

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. To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1). ApoE(-/-) mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle. 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. HIF-1-mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase inactivation may contribute to atherosclerosis in patients with sleep apnea.