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(Circulation Research. 2008;103:1173.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Dyslipidemia and Atherosclerosis Induced by Chronic Intermittent Hypoxia Are Attenuated by Deficiency of Stearoyl Coenzyme A Desaturase

Vladimir Savransky, Jonathan Jun, Jianguo Li, Ashika Nanayakkara, Shannon Fonti, Ann B. Moser, Kimberly E. Steele, Michael A. Schweitzer, Susheel P. Patil, Sanjay Bhanot, Alan R. Schwartz, Vsevolod Y. Polotsky

From the Department of Medicine (V.S., J.J., J.L., A.N., S.F., S.P.P., A.R.S., V.Y.P.), Division of Pulmonary and Critical Care Medicine; Kennedy Krieger Institute (A.B.M.); and Department of Surgery (K.E.S., M.A.S.), Johns Hopkins University, Baltimore, Md; and Isis Pharmaceuticals Inc (S.B.), Carlsbad, Calif.

Correspondence to Vsevolod Y. Polotsky, MD, PhD, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail vpolots1{at}jhmi.edu

Obstructive sleep apnea leads to chronic intermittent hypoxia (CIH) and is associated with atherosclerosis. We have previously shown that C57BL/6J mice exposed to CIH and a high-cholesterol diet develop dyslipidemia, atherosclerosis of the aorta, and upregulation of a hepatic enzyme of lipoprotein secretion, stearoyl coenzyme A desaturase 1 (SCD-1). We hypothesized that (1) SCD-1 deficiency will prevent dyslipidemia and atherosclerosis during CIH; and (2) human OSA is associated with dyslipidemia and upregulation of hepatic SCD. C57BL/6J mice were exposed to CIH or normoxia for 10 weeks while being treated with either SCD-1 or control antisense oligonucleotides. Obese human subjects underwent sleep study and bariatric surgery with intraoperative liver biopsy. In mice, hypoxia increased hepatic SCD-1 and plasma very-low-density lipoprotein cholesterol levels and induced atherosclerosis lesions in the ascending aorta (the cross-section area of 156514±57408 µm²), and descending aorta (7.0±1.2% of the total aortic surface). In mice exposed to CIH and treated with SCD-1 antisense oligonucleotides, dyslipidemia and atherosclerosis in the ascending aorta were abolished, whereas lesions in the descending aorta showed 56% reduction. None of the mice exposed to normoxia developed atherosclerosis. In human subjects, hepatic SCD mRNA levels correlated with the degree of nocturnal hypoxemia (r=0.68, P=0.001). Patients exhibiting oxyhemoglobin desaturations at night showed higher plasma triglyceride and low-density lipoprotein cholesterol levels, compared to subjects without hypoxemia. In conclusion, CIH is associated with dyslipidemia and overexpression of hepatic SCD in both humans and mice alike; SCD-1 deficiency attenuates CIH-induced dyslipidemia and atherosclerosis in mice.

Key Words: atherosclerosis • hypercholesterolemia • hypoxia • lipoproteins • obstructive sleep apnea

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