Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4

Luciano F. Drager, Qiaoling Yao, Karen L. Hernandez, Mi Kyung Shin, Shannon Bevans-Fonti, Jason Gay, Thomas E. Sussan, Jonathan C. Jun, Allen C. Myers, Gunilla Olivecrona, Alan R. Schwartz, Nils Halberg, Philipp E. Scherer, Gregg L. Semenza, David R. Powell, Vsevolod Y. Polotsky

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)240-248
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume188
Issue number2
DOIs
StatePublished - Jul 15 2013

Keywords

  • Adipose tissue
  • Hypoxia-inducible factor-1
  • Lipoprotein clearance
  • Lipoprotein lipase
  • Sleep apnea

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Drager, L. F., Yao, Q., Hernandez, K. L., Shin, M. K., Bevans-Fonti, S., Gay, J., Sussan, T. E., Jun, J. C., Myers, A. C., Olivecrona, G., Schwartz, A. R., Halberg, N., Scherer, P. E., Semenza, G. L., Powell, D. R., & Polotsky, V. Y. (2013). Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4. American journal of respiratory and critical care medicine, 188(2), 240-248. https://doi.org/10.1164/rccm.201209-1688OC