A model of sleep-disordered breathing  in the C57BL/6J mouse

Tagaito, Yugo; Polotsky, Vsevolod Y.; Campen, Matthew J.; Wilson, Jessica A.; Balbir, Alexander; Smith, Philip L.; Schwartz, Alan R.; O’Donnell, Christopher P.

doi:10.1152/jappl.2001.91.6.2758

Cited by 112 publications

(87 citation statements)

References 41 publications

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“…21 Oxidative stress has been implicated in pathogenesis of systemic complications of CIH, including neurological impairments and atherosclerosis. [37][38][39] We provide the first direct experimental evidence that CIH, similar to that observed in severe OSA, 40 induces a nearly 2-fold increase in lipid peroxidation in the liver (Fig. 4A), which may cause impairment of the cellular membranes and lead to liver injury.…”

Section: Discussionsupporting

confidence: 57%

Chronic intermittent hypoxia predisposes to liver injury

et al. 2007

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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

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Section: Discussionsupporting

confidence: 57%

Chronic intermittent hypoxia predisposes to liver injury

et al. 2007

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“…To our knowledge, this is the first study reporting the development of systemic hypertension in a mouse model of SA, where mice are exposed to intermittent episodes of low O 2 (from 20.9 to 5%) and elevated CO 2 (from 0 to 5%). However, previous reports show that intermittent hypoxia (nadir O 2 of 5%) without CO 2 supplementation also induces systemic hypertension in mice (51,58).…”

Section: Discussionmentioning

confidence: 90%

NFATc3 is required for intermittent hypoxia-induced hypertension

Garcı́a¹,

Duling²,

Alò³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Sleep apnea, defined as intermittent respiratory arrest during sleep, is associated with increased incidence of hypertension and peripheral vascular disease. Exposure of rodents to brief periods of intermittent hypercarbia/hypoxia (H-IH) during sleep mimics the cyclical hypoxia-normoxia of sleep apnea. Endothelin-1, an upstream activator of nuclear factor of activated T cells (NFAT), is increased during H-IH. Therefore, we hypothesized that NFATc3 is activated by H-IH and is required for H-IH-induced hypertension. Consistent with this hypothesis, we found that H-IH (20 brief exposures per hour to 5% O2-5% CO2 for 7 h/day) induces systemic hypertension in mice [mean arterial pressure (MAP) ϭ 97 Ϯ 2 vs. 124 Ϯ 2 mmHg, P Ͻ 0.05, n ϭ 5] and increases NFATc3 transcriptional activity in aorta and mesenteric arteries. Cyclosporin A, an NFAT inhibitor, and genetic ablation of NFATc3 [NFATc3 knockout (KO)] prevented NFAT activation. More importantly, H-IHinduced hypertension was attenuated in cyclosporin A-treated mice and prevented in NFATc3 KO mice. MAP was significantly elevated in wild-type mice (⌬ ϭ 23.5 Ϯ 6.1 mmHg), but not in KO mice (⌬ ϭ Ϫ3.9 Ϯ 5.7). These results indicate that H-IH-induced increases in MAP require NFATc3 and that NFATc3 may contribute to the vascular changes associated with H-IH-induced hypertension.nuclear factor of activated T cells; hypercarbic; mouse; endothelin-1; sleep apnea SLEEP APNEA (SA), defined as intermittent respiratory arrest during sleep, affects up to 20% of the adult population. Among the major consequences of SA are decreased O 2 saturation (hypoxia) and increased CO 2 saturation (hypercapnia). In SA patients, incidence of hypertension, peripheral vascular disease, stroke, and sudden cardiac death is increased (for review see Refs. 21 and 44). Thus SA appears to directly initiate vascular changes that predispose individuals to cardiovascular disease.Recently, it was demonstrated that exposure of rodents to periods of intermittent hypoxia with CO 2 supplementation [intermittent hypercarbia/hypoxia (H-IH)] during sleep mimics the cyclical hypoxia-normoxia of SA. In rats exposed to H-IH, blood pressure (34, 35) and circulating endothelin-1 (ET-1) are elevated (35), vasoconstrictor sensitivity to ET-1 is increased (2), and blood pressure is normalized with ET antagonists (35). These studies, together with clinical studies showing increased circulating ET-1 in SA (10, 55), suggest that augmented ET-1 vasoconstriction contributes to SA hypertension. The sustained increased blood pressure observed in SA patients and animal models also appears to involve activation of the sympathetic nervous and renin-angiotensin systems and diminished activity of nitric oxide synthase (for review see Refs. 44 and 52).ET-1 acts through G␣ q -coupled receptors as a Ca 2ϩ -mobilizing agent and as a potent activator of the nuclear factor of activated T cells (NFAT) (1, 25, 57). ANG II, glucose through UTP release, and ␣ 1 -adrenergic agonists are also potent stimuli of NFAT activation (1,25,27,46,57).NFAT...

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“…A mouse model of sleep apnea based on repeated exposures to episodes of intermittent hypoxia has allowed for laboratory investigations of proposed morbidities of sleep apnea, [123][124] including endothelial dysfunction, cardiovascular abnormalities, immunological disorders, and kidney diseases. [125][126][127] The epidemiological and cohort studies linking sleep apnea to kidney disease led Sun and colleagues to examine the effects of sleep apnea on renal function and morphology in a mouse model of intermittent hypoxia.…”

Section: Animal Model Of Sleep Apnea-induced Renal Damagementioning

confidence: 99%