NADPH Oxidase Mediates Hypersomnolence and Brain Oxidative Injury in a Murine Model of Sleep Apnea

Zhan, Guanxia; Serrano, Faridis; Fenik, Polina; Hsu, Ray T.; Kong, Leopold; Praticò, Domenico; Klann, Eric; Veasey, Sigrid C.

doi:10.1164/rccm.200504-581oc

Cited by 232 publications

(206 citation statements)

References 57 publications

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“…CIH in mice increases MDA and isoprostane levels in the brain as well as activity of NADPH oxidase, an enzyme-producing superoxide. 19,20 CIH in rats increases MDA levels in the myocardium and decreases activity of superoxide dismutase, an important endogenous antioxidant. 21 Oxidative stress has been implicated in pathogenesis of systemic complications of CIH, including neurological impairments and atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Chronic intermittent hypoxia predisposes to liver injury

et al. 2007

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“…Having identified NADPH oxidase as an important contributor to LTIH wake-active neuron oxidation and wake impairments (Zhan et al, 2005b), the presence of three NADPH oxidase subunits was looked for in cholinergic, dopaminergic, histaminergic, noradrenergic, orexinergic, and serotonergic wake neurons. Primary antibodies selected were anti-p47 phox (rabbit, 1:500; 07-001, Upstate Biotechnology, Lake Placid, NY), anti-p67 phox (rabbit, 1:500; 07-002, Upstate Biotechnology), and anti-gp91 phox (mouse,1:500, clone 53; BD Biosciences, Franklin Lakes, NJ) and were used with the above wake neuron identifying antibodies and Alexa Fluor secondaries to label select groups of wake neurons and each NADPH oxidase subunit.…”

Section: Methodsmentioning

confidence: 99%

“…To determine whether NADPH oxidase inhibition could prevent catecholaminergic neuronal demise, a third series of mice was implanted with osmotic pumps filled with NADPH oxidase inhibitor, apocynin (Sigma-Aldrich, St Louis, MO) concentrated to deliver subcutaneously 3 mg/kg/d drug (sham LTIM, n ϭ 4; LTIH, n ϭ 4; LTIH apocynin, n ϭ 4; LTIH dimethyl sulfoxide/vehicle, n ϭ 4) using a previously established dosing (Jacobson et al, 2003). The selected dose has been shown to prevent LTIH hypersomnolence in mice (Zhan et al, 2005b). Three days after pump implantation, mice were exposed to LTIH for a period of 8 weeks, exchanging pumps every 2 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we identified NADPH oxidase as a major contributor to both the oxidative injury and the wake impairments in the model of sleep apnea oxygenation. Specifically, mice with transgenic absence of a catalytic subunit of NADPH oxidase, Nox 2, and mice with pharmacological inhibition of Nox 2 catalysis throughout exposure to hypoxia/reoxygenation confer resistance to both wake impairments and oxidation (Zhan et al, 2005b). Therefore, NADPH oxidase may contribute to the vulnerability of select neurons to hypoxia/reoxygenation injury.…”

Section: Introductionmentioning

confidence: 99%

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Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Zhu¹,

Fenik²,

Zhan³

et al. 2007

J. Neurosci.

165

118

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The presence of refractory wake impairments in many individuals with severe sleep apnea led us to hypothesize that the hypoxia/ reoxygenation events in sleep apnea permanently damage wake-active neurons. We now confirm that long-term exposure to hypoxia/ reoxygenation in adult mice results in irreversible wake impairments. Functionality and injury were next assessed in major wake-active neural groups. Hypoxia/reoxygenation exposure for 8 weeks resulted in vacuolization in the perikarya and dendrites and markedly impaired c-fos activation response to enforced wakefulness in both noradrenergic locus ceruleus and dopaminergic ventral periaqueductal gray wake neurons. In contrast, cholinergic, histaminergic, orexinergic, and serotonergic wake neurons appeared unperturbed. Six month exposure to hypoxia/reoxygenation resulted in a 40% loss of catecholaminergic wake neurons. Having previously identified NADPH oxidase as a major contributor to wake impairments in hypoxia/reoxygenation, the role of NADPH oxidase in catecholaminergic vulnerability was next addressed. NADPH oxidase catalytic and cytosolic subunits were evident in catecholaminergic wake neurons, where hypoxia/reoxygenation resulted in translocation of p67 phox to mitochondria, endoplasmic reticulum, and membranes. Treatment with a NADPH oxidase inhibitor, apocynin, throughout hypoxia/reoxygenation exposures conferred protection of catecholaminergic neurons. Collectively, these data show that select wake neurons, specifically the two catecholaminergic groups, can be rendered persistently impaired after long-term exposure to hypoxia/reoxygenation, modeling sleep apnea; wake impairments are irreversible; catecholaminergic neurons are lost; and neuronal NADPH oxidase contributes to this injury. It is anticipated that severe obstructive sleep apnea in humans destroys catecholaminergic wake neurons.

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“…Very little is known about this interaction [49,50]. Hypoxia induces oxidative stress in the brain [51,52] and is associated with increased levels of proinflammatory cytokines, such as TNF-α in pig [53], in humans [54] and in mice [55]. Indeed, the levels of TNF-α may remain elevated in the affected brain tissue for at least 24 h after an ischemic insult [16,56] and TNF-α itself causes oxidative stress in the brain [57].…”

Section: Tnf-α and Hypoxia In The Cnsmentioning

confidence: 99%

Targeting tumour necrosis factor-α in hypoxia and synaptic signalling

O’Connor

2013

Ir J Med Sci

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Tumor necrosis factor (TNF)-α is a proinflammatory cytokine, which is synthesised and released in the brain by astrocytes, microglia and neurons in response to numerous internal and external stimuli. It is involved in many physiological and pathophysiological processes such as gene transcription, cell proliferation, apoptosis, synaptic signalling and neuroprotection. The complex actions of TNF-α in the brain are under intense investigation. TNF-α has the ability to induce selective necrosis of some cells whilst sparing others and this has led researchers to discover multiple activated signalling cascades. In many human diseases including acute stroke and inflammation and those involving hypoxia, levels of TNF-α are increased throughout different brain regions. TNF-α signalling may also have several positive and negative effects on neuronal function including glutamatergic synaptic transmission and plasticity. Exogenous TNF-α may also exacerbate the neuronal response to hypoxia. This review will summarise the actions of TNF-α in the central nervous system on synaptic signalling and its effects during hypoxia.

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NADPH Oxidase Mediates Hypersomnolence and Brain Oxidative Injury in a Murine Model of Sleep Apnea

Cited by 232 publications

References 57 publications

Chronic intermittent hypoxia predisposes to liver injury

Chronic intermittent hypoxia predisposes to liver injury

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Targeting tumour necrosis factor-α in hypoxia and synaptic signalling

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