Rationale: Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is associated with hyperlipidemia, atherosclerosis, and a high cardiovascular risk. A causal link between obstructive sleep apnea and atherosclerosis has not been established. Objectives: The objective of the present study was to examine whether CIH may induce atherosclerosis in C57BL/6J mice. Methods: Forty male C57BL/6J mice, 8 weeks of age, were fed either a high-cholesterol diet or a regular chow diet and subjected either to CIH or intermittent air (control conditions) for 12 weeks. Measurements and Main Results: Nine of 10 mice simultaneously exposed to CIH and high-cholesterol diet developed atherosclerotic lesions in the aortic origin and descending aorta. In contrast, atherosclerosis was not observed in mice exposed to intermittent air and a high-cholesterol diet or in mice exposed to CIH and a regular diet. A high-cholesterol diet resulted in significant increases in serum total and low-density lipoprotein cholesterol levels and a decrease in high-density lipoprotein cholesterol. Compared with mice exposed to intermittent air and a high-cholesterol diet, combined exposure to CIH and a high-cholesterol diet resulted in marked progression of dyslipidemia with further increases in serum total cholesterol and low-density lipoprotein cholesterol (124 ؎ 4 vs. 106 ؎ 6 mg/dl; p Ͻ 0.05), a twofold increase in serum lipid peroxidation, and up-regulation of an important hepatic enzyme of lipoprotein secretion, stearoyl-coenzyme A desaturase-1. Conclusions: CIH causes atherosclerosis in the presence of dietinduced dyslipidemia.Keywords: obstructive sleep apnea; lipids; hypoxia; mouse; stearoylcoenzyme A desaturaseObstructive sleep apnea (OSA) is characterized by recurrent collapse of the upper airway during sleep, leading to chronic intermittent hypoxia (CIH) (1). OSA has been associated with an increased risk of hypertension, type II diabetes, angina, myocardial infarction, congestive heart failure, stroke, and fatal cardiovascular events, independent of underlying obesity (2-5).Poor cardiovascular outcomes may be related to the high prevalence of atherosclerosis in patients with OSA. Studies have shown independent associations between hypoxic stress of OSA and increased carotid artery intima-media thickness (6) as well as progressive narrowing of the coronary artery lumens (7).
Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH). OSA is associated with nonalcoholic steatohepatitis (NASH) in obese subjects. The aim of this study was to investigate the effects of CIH on the liver in the absence of obesity. Lean C57BL/6J mice (n ؍ 15) on a regular chow diet were exposed to CIH for 12 weeks and compared with pair-fed mice exposed to intermittent air (IA, n ؍ 15). CIH caused liver injury with an increase in serum ALT (224 ؎ 39 U/l versus 118 ؎ 22 U/l in the IA group, P < 0.05), whereas AST and alkaline phosphatase were unchanged. CIH also induced hyperglycemia, a decrease in fasting serum insulin levels, and mild elevation of fasting serum total cholesterol and triglycerides (TG). Liver TG content was unchanged, whereas cholesterol content was decreased. Histology showed swelling of hepatocytes, no evidence of hepatic steatosis, and marked accumulation of glycogen in hepatocytes. CIH led to lipid peroxidation of liver tissue with a malondialdehyde ( O bstructive sleep apnea (OSA) is characterized by recurrent collapse of the upper airway during sleep, leading to chronic intermittent hypoxia (CIH). 1 OSA is a common disease, present in 2% of women and 4% of men in the general U.S. population; however, the prevalence rises to 40% to 60% in obese individuals. 2,3 CIH of OSA has been associated with an increased risk of hypertension, type 2 diabetes, dyslipidemia, and atherosclerosis, independent of underlying obesity. 2,4-9 Moreover, studies in rodent models of intermittent hypoxia (IH) demonstrated that CIH can cause hypertension, 10 insulin resistance, 11 and dyslipidemia. 12,13 Thus, CIH of OSA has been implicated in causality of cardiovascular and metabolic disorders, independent of obesity.An emerging body of evidence indicates that OSA is associated with non-alcoholic steatohepatitis (NASH) and chronic liver injury in obese individuals. 14,15 Whether OSA can confer risk of NASH, independent of obesity, remains unclear. Two major mechanisms have been implicated in NASH: (1) hepatic steatosis, which is linked to insulin resistance; and (2) increased levels of oxidative stress with liver injury and subsequent inflammation. 16,17 We previously showed that CIH leads to progression of hepatic steatosis and insulin resistance in leptin-deficient obese mice. 12 However, the effects of CIH on hepatic lipids in the absence of obesity have not been examined. Whereas OSA and CIH induce oxidative stress and inflammation in multiple organs and tissues, 18-21 the impact
Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P < 0.01) and AST (637 +/- 37 U/l vs. 175 +/- 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1beta, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-alpha; and an increase in alpha1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.
Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH) and associated with dysregulation of lipid metabolisms and atherosclerosis. Causal relationships between OSA and metabolic abnormalities have not been established because of confounding effects of underlying obesity. The goal of the study was to determine if CIH causes lipid peroxidation and dyslipidemia in the absence of obesity and whether the degrees of dyslipidemia and lipid peroxidation depend on the severity of hypoxia. Lean C57BL/6J mice were exposed to CIH for 4 wk with a fractional inspired O2 (FI(O2)) nadir of either 10% (moderate CIH) or 5% (severe CIH). Mice exposed to severe CIH exhibited significant increases in fasting serum levels of total cholesterol (129 +/- 2.9 vs. 113 +/- 2.8 mg/dl in control mice, P < 0.05) and low-density lipoprotein cholesterol (85.7 +/- 8.9 vs. 56.4 +/- 9.7 mg/dl, P < 0.05) in conjunction with a 1.5- to 2-fold increase in lipoprotein secretion, and upregulation of hepatic stearoyl coenzyme A desaturase 1 (SCD-1). Severe CIH also markedly increased lipid peroxidation in the liver (malondialdehyde levels of 94.4 +/- 5.4 vs. 57.4 +/- 5.2 nmol/mg in control mice, P < 0.001). In contrast, moderate CIH did not induce hyperlipidemia or change in hepatic SCD-1 levels but did cause lipid peroxidation in the liver at a reduced level relative to severe CIH. In conclusion, CIH leads to hypercholesterolemia and lipid peroxidation in the absence of obesity, and the degree of metabolic dysregulation is dependent on the severity of the hypoxic stimulus.
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