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

Abstract

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 156514Ϯ57408 m 2 ), and descending aorta (7.0Ϯ1.2% 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 (rϭ0.68, Pϭ0.001). 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 Ⅲ hypercholesterolemia Ⅲ hypoxia Ⅲ lipoproteins Ⅲ obstructive sleep apnea O bstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH) during sleep. 1 OSA occurs in 9% of women and 24% of men in the United States, but the prevalence exceeds 30% to 50% in the obese population. 2,3 OSA poses significant cardiovascular risk, which has been attributed to the high prevalence of atherosclerosis in patients with OSA. 4 -6 OSA is associated with dyslipidemia, lipid peroxidation, and vascular inflammation, all of which induce atherosclerosis. 7-10 Recent studies have shown independent associations between the hypoxic stress of OSA and increased carotid artery intima-media thickness 11,12 that is reversed by treatment with continuous positive airway pressure. 13 Our group has previously explored relationships between CIH and atherosclerosis using a mouse model of CIH that mimics the oxygen profile in patients with severe OSA. 14,15 We have shown that CIH induces atherosclerosis in C57BL/6J mice on a high-cholesterol diet. 16 We have also found that the development of atherosclerosis during CIH was associated with increases in lipoprotein secretion, plasma very-low-density lipoprotein VLDL levels, an...

Obstructive Sleep Apnea–Hypopnea and Incident Stroke

“…OSA may promote generalized atherosclerosis through effects of intermittent hypoxemia, which activates the transcription factors hypoxia-inducible factor-1 and nuclear factor-kB, which, in turn, induce the expression of inflammatory cytokines and adhesion molecules implicated in atherosclerosis. Intermittent hypoxemia also has been shown in mice models to induce the hepatic enzyme, stearoyl coenzyme desaturase, leading to dyslipidemia and atherosclerotic lesions (24). The potential importance of OSA in increasing stroke risk through atherogenic pathways is consistent with the reported higher prevalence of internal carotid artery atherosclerotic lesions in stroke patients with compared with those without OSA (25).…”

Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice

“…Several studies reported such anomalies of lipid metabolism in both OSA-patients 8 and mice exposed to IH 7 , IH-related atherosclerosis appearing to be closely associated with lipid alterations 10,11,21 . However in our study, 14 days of IH in HCD-fed mice accelerated atherosclerosis development independently of total 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 cholesterol levels.…”

Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art

“…Most studies have not demonstrated significant differences in the prevalence of dyslipidemia between COPD patients and control subjects [56]. Chronic intermittent hypoxia has been shown to upregulate a hepatic enzyme of lipoprotein secretion, leading to elevated low-density lipoprotein cholesterol levels in patients with obstructive sleep apnea (OSA) [57]. This is a potential mechanism for some observations of higher cholesterol values in selected very severe COPD patients.…”