title: Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase.
abstract: 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 microm(2)), 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.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Savransky
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jun
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.forename: Ashika
authors.initials: A
authors.lastname: Nanayakkara
authors.forename: Shannon
authors.initials: S
authors.lastname: Fonti
authors.forename: Ann B
authors.initials: AB
authors.lastname: Moser
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Steele
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schweitzer
authors.forename: Susheel P
authors.initials: SP
authors.lastname: Patil
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Alan R
authors.initials: AR
authors.lastname: Schwartz
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D050197:Atherosclerosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D002784:Cholesterol / Q000009:adverse effects / Q000494:pharmacology; D015243:Cholesterol, VLDL / Q000097:blood; D002908:Chronic Disease; D004036:Diet, Atherogenic; D050171:Dyslipidemias / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D010845:Obesity Hypoventilation Syndrome / Q000201:enzymology* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010108:Oxyhemoglobins / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015243:Cholesterol, VLDL; D016376:Oligonucleotides, Antisense; D010108:Oxyhemoglobins; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; C523776:SCD1 protein, human; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase