Impact Of Intermittent Hypoxia Research Articles

Intermittent hypoxia induces fibroblast activation: An in vitro approach in NIH/3T3 cells

Obstructive sleep apnea (OSA) is recognized as an independent cardiovascular (CV) risk factor. Intermittent hypoxia (IH), the landmark feature of OSA, represents the major detrimental factor triggering CV complications. In rodent models, IH contributes to cardiac remodeling, mainly characterized by early interstitial fibrosis. However, the direct effect of IH on cardiac fibrosis, as well as involved mechanisms are unclear. The aim of this study is to investigate in vitro whether IH induces fibroblast activation. NIH/3T3 murine fibroblasts were exposed to normoxic condition (N) or fast IH cycles, including 5-min normoxia (16% O2) followed by 5-min hypoxia (2% O2), in the presence or not of 10 ng/ml transforming growth factor (Tgf-∝). Cell proliferation was assessed after 48 h N or IH exposure by MTT assay; cell migration was evaluated during 12 h epxosure by scratch assay; mRNA expression of several markers of fibrosis was evaluated after 6 h exposure. Fibroblast differentiation was evaluated through α Smooth Muscle Actin (Acta2) mRNA expression and fibrosis through expression of Collagen 1 (Col1a1), lysyl oxidase (Lox), Tgf∝ and Tgf∝ receptor (Tgf-∝R). Data were analyzed by 2-ways Anova (Impact of IH and Tgf-β), followed by a Tukey post-hoc test. Our results confirm the well-known role of Tgf-∝ on fibroblast activation, characterized by increased proliferation (P = 0.004) and mRNA expression of Acta2 (P = 0.002), Col1a1 (P = 0.008) and Lox (P = 0.04). Independently of Tgf-β, IH does not increase cell proliferation, tends to increase fibroblasts migration (P = 0.1) and significantly increases mRNA expression of Acta2 (P = 0.002) and Col1a1 (P = 0.05), whereas increases in Lox and Tgf-β expression do not reach significance (P = 0.06 and P = 0.08). Interestingly, concomitant stimulation with Tgf-β and IH does not potentiate cell proliferation and migration, but synergistically increases Acta2, Col1a1 and Lox mRNA expression. Our in vitro results shows that IH induces fibroblast activation, promoting migration, differentiation into myofibroblast and expression of fibrotic markers. Furthermore, IH and Tgf-∝ seem to exert synergistic effects on fibrosis. Further studies are needed to understand specific mechanisms involved in IH-induced fibrosis.

The Impact of Intermittent Hypoxia on Metabolism and Cognition.

Intermittent hypoxia (IH), one of the primary pathologies of sleep apnea syndrome (SAS), exposes cells throughout the body to repeated cycles of hypoxia/normoxia that result in oxidative stress and systemic inflammation. Since SAS is epidemiologically strongly correlated with type 2 diabetes/insulin resistance, obesity, hypertension, and dyslipidemia included in metabolic syndrome, the effects of IH on gene expression in the corresponding cells of each organ have been studied intensively to clarify the molecular mechanism of the association between SAS and metabolic syndrome. Dementia has recently been recognized as a serious health problem due to its increasing incidence, and a large body of evidence has shown its strong correlation with SAS and metabolic disorders. In this narrative review, we first outline the effects of IH on the expression of genes related to metabolism in neuronal cells, pancreatic β cells, hepatocytes, adipocytes, myocytes, and renal cells (mainly based on the results of our experiments). Next, we discuss the literature regarding the mechanisms by which metabolic disorders and IH develop dementia to understand how IH directly and indirectly leads to the development of dementia.

Impact of intermittent hypoxia on ischemic cardiomyopathy progression: Role of insulin and adrenergic cross-talk

Patients with obstructive sleep apnea (OSA) exhibit poor prognosis after myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark feature of OSA, promotes sympathetic hyperactivity, hyperinsulinemia and insulin resistance, and has been identified as a major contributor to post-MI cardiac remodeling and contractile dysfunction. We hypothesize that IH-induced sympathetic activation and insulin resistance lead to desensitization of cardiac adrenergic and insulin signaling pathways, which contribute to the progression of ischemic cardiomyopathy. MI is induced in C57bl6 mice by permanent ligation of the left coronary artery. Mice were then randomized to IH (21–5% FiO 2 , 60 s cycle, 8 h/day) or normoxia for up to 6 weeks. Longitudinal follow-up of mice includes evaluation of systemic insulin sensitivity (dynamic insulin tolerance test), cardiac sympathetic activity, spectral analysis of heart rate variability (HRV) and determination of cardiac function/remodeling (echocardiography). Following the completion of IH protocol, cardiac interstitial fibrosis and hypertrophy are evaluated by RT-qPCR and histology (Sirius Red and WGA staining, respectively). Assessment of adrenergic and insulin signaling pathways and there cross-talk are performed by Western blot (WB). IH worsens MI-induced cardiac contractile dysfunction in mice, resulting in a significant decrease in ejection fraction (19.4 ± 2.1% vs. 33.3 ± 3.9% in IH vs. N respectively, P < 0.05). MI causes significant cardiac remodeling in both N and IH groups, characterized by upregulation of several markers of cardiac fibrosis (Col1a1, Col3a1) and hypertrophy (Acta1, MyH7), which tend to be higher in IH compared to N. In our MI model, IH does not induce significant systemic insulin resistance and tends to increase LF power with no significant modification of LF/HF ratio compared to N mice. Histological experiments will be performed to confirm IH-induced aggravation of post-MI cardiac remodeling and ongoing WB will determine whether IH specifically affects cardiac insulin and adrenergic signaling. These findings demonstrate that IH is responsible for aggravation of contractile function in our ischemic cardiomyopathy mice model. Ongoing experiments will determine whether alteration of adrenergic and insulin signalling are involved as contributing mechanisms.

Intermittent Hypoxia Inhibits Hepatic CYP1a2 Expression and Delays Aminophylline Metabolism.

Purpose In this study, we aimed to determine the effects of intermittent hypoxia (IH) on hepatic cytochrome P450 1A2 (CYP1A2) expression and the pharmacokinetics of CYP1A2-mediated aminophylline and warfarin in vitro and in a rabbit model of obstructive sleep apnea. Materials Human normal liver (LO-2) cells were exposed to 30 min each of 1%, 1–21%, 21%, and 21–1% O2, and then, CYP1A2 expression and drug concentrations were analyzed. We compared the pharmacokinetic parameters of drugs administered to normoxic rabbits and those exposed to 10 min of IH during which the oxygen level fluctuated from 21% to 8%–10% (n = 10 per group). Results. The expression of CYP1A2 protein in vitro was significantly reduced in the IH compared with the normoxic cells (0.56 ± 0.11 vs. 1.27 ± 0.17, p < 0.001). Aminophylline was more abundant in cell culture supernatants after 48 h of IH than in those under normoxia. The T1/2, AUC0–24 h, and Ke values for aminophylline were significantly higher in the IH group. Conclusion Intermittent hypoxia inhibits hepatic CYP1A2 expression and delays aminophylline metabolism, suggesting that the impact of IH on the expression of CYP enzymes should be closely monitored in clinical practice.

Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is widely known for its multiple systems damage, especially neurocognitive deficits in children. Since their discovery, adenosine A2A receptors (A2ARs) have been considered as key elements in signaling pathways mediating neurodegenerative diseases such as Huntington's and Alzheimer's, as well as cognitive function regulation. Herein, we investigated A2AR role in cognitive impairment induced by chronic intermittent hypoxia (CIH). Mice were exposed to CIH 7 h every day for 4 weeks, and intraperitoneally injected with A2AR agonist CGS21680 or A2AR antagonist SCH58261 half an hour before IH exposure daily. The 8-arm radial arm maze was utilized to assess spatial memory after CIH exposures.To validate findings using pharmacology, the impact of intermittent hypoxia was investigated in A2AR knockout mice. CIH-induced memory dysfunction was manifested by increased error rates in the radial arm maze test. The behavioral changes were associated with hippocampal pathology, neuronal apoptosis, and synaptic plasticity impairment. The stimulation of adenosine A2AR exacerbated memory impairment with more serious neuropathological damage, attenuated long-term potentiation (LTP), syntaxin down-regulation, and increased BDNF protein. Moreover, apoptosis-promoting protein cleaved caspase-3 was upregulated while anti-apoptotic protein Bcl-2 was downregulated. Consistent with these findings, A2AR inhibition with SCH58261 and A2AR deletion exhibited the opposite result. Overall, these findings suggest that A2AR plays a critical role in CIH-induced impairment of learning and memory by accelerating hippocampal neuronal apoptosis and reducing synaptic plasticity. Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice.

Impact of intermittent hypoxia on human vascular responses during sleep

Exposure to intermittent hypoxia (IH) ≥15 times per hour is believed to be the primary mechanism for the increased risk of cerebrovascular and cardiovascular disease in patients with moderate to severe sleep apnea. Human experimental models of IH used to investigate this link have been predominantly employed during wakefulness, which limits extrapolation of findings to sleep apnea where IH occurs during sleep. Moreover, how IH impacts vascular regulation during sleep has not been measured quantitatively. Therefore, the objective of this study was to assess the impact sleep accompanied by IH on vascular responses to hypoxia and hypercapnia during sleep. Ten males performed two randomly scheduled 6-h overnight sleep studies. One sleep study was performed in room air (normoxia) and the other sleep study was performed during isocapnic IH (60 s hypoxia-60 s normoxia). On each night, cerebrovascular (peak blood velocity through the middle cerebral artery (V¯P); transcranial Doppler ultrasound) and cardiovascular (blood pressure, heart rate) responses to hypoxia and hypercapnia were measured before sleep onset (PM-Awake), within the first 2 h of sleep (PM-Asleep), in the 5th (out of 6) hours of sleep (AM-Asleep) and after being awoken in the morning (AM-Awake). Sleep accompanied by IH had no impact on the V¯P and blood pressure responses to hypoxia and hypercapnic at any timepoint (p ≥ 0.103 for all responses). However, the AM-Awake heart rate response to hypoxia was greater following sleep in IH compared to sleep in normoxia. Independent of the sleep environment, the V¯P response to hypoxia and hypercapnia were reduced during sleep. In conclusion, cerebral blood flow responses are reduced during sleep compared to wakefulness, but 6 h of sleep accompanied by IH does not alter cerebrovascular and cardiovascular response to hypoxia and hypercapnia during wakefulness or sleep in healthy young humans. However, it is likely that longer exposure to IH during sleep (i.e., days-to-weeks) is required to better elucidate IH's impact on vascular regulation in humans.

Sleep Apnea in Idiopathic Pulmonary Fibrosis: A Molecular Investigation in an Experimental Model of Fibrosis and Intermittent Hypoxia.

Background: High prevalence of obstructive sleep apnea (OSA) is reported in incident and prevalent forms of idiopathic pulmonary fibrosis (IPF). We previously reported that Intermittent Hypoxia (IH), the major pathogenic element of OSA, worsens experimental lung fibrosis. Our objective was to investigate the molecular mechanisms involved. Methods: Impact of IH was evaluated on C57BL/6J mice developing lung fibrosis after intratracheal instillation of Bleomycin (BLM). Mice were Pre-exposed 14 days to IH before induction of lung fibrosis or Co-challenged with IH and BLM for 14 days. Weight loss and survival were daily monitored. After experimentations, lungs were sampled for histology, and protein and RNA were extracted. Results: Co-challenge or Pre-exposure of IH and BLM induced weight loss, increased tissue injury and collagen deposition, and pro-fibrotic markers. Major worsening effects of IH exposure on lung fibrosis were observed when mice were Pre-exposed to IH before developing lung fibrosis with a strong increase in sXBP1 and ATF6N ER stress markers. Conclusion: Our results showed that IH exacerbates BLM-induced lung fibrosis more markedly when IH precedes lung fibrosis induction, and that this is associated with an enhancement of ER stress markers.

Intermittent Hypoxia causes targeted disruption to NMDA receptor dependent synaptic plasticity in area CA1 of the hippocampus

Changed NMDA receptor (NMDAr) physiology is implicated with cognitive deficit resulting from conditions ranging from normal aging to neurological disease. Using intermittent hypoxia (IH) to experimentally model untreated sleep apnea, a clinical condition whose comorbidities include neurocognitive impairment, we recently demonstrated that IH causes a pro-oxidant condition that contributes to deficits in spatial memory and in NMDAr-dependent long-term potentiation (LTP). However, the impact of IH on additional forms of synaptic plasticity remains ill-defined. Here we show that IH prevents the induction of NMDAr-dependent LTP and long-term depression (LTD) in hippocampal brain slices from mice exposed to ten days of IH (IH10) yet spares NMDAr-independent forms of synaptic plasticity. Deficits in synaptic plasticity were accompanied by a reduction in hippocampal GluN1 expression. Acute manipulation of redox state using the reducing agent, Dithiothreitol (DTT) stimulated the NMDAr-dependent fEPSP following IH10. However, acute use of either DTT or MnTMPyP did not restore NMDAr-dependent synaptic plasticity after IH10 or prevent the IH-dependent reduction in GluN1, the obligatory subunit of the NMDAr. In contrast, MnTMPyP during IH10 (10-MnTMPyP), prevented the suppressive effects of IH on both NMDAr-dependent synaptic plasticity and GluN1 expression. These findings indicate that while the IH-dependent pro-oxidant state causes reversible oxidative neuromodulation of NMDAr activity, acute manipulation of redox state is ineffective in rescuing two key effects of IH related to the NMDAr within the hippocampus. These IH-dependent changes associated with the NMDAr may be a primary avenue by which IH enhances the vulnerability to impaired learning and memory when sleep apnea is left untreated in normal aging and in disease.

Short-term intermittent hypoxia induces simultaneous systemic insulin resistance and higher cardiac contractility in lean mice.

BackgroundIntermittent hypoxia (IH) is the major feature of obstructive sleep apnea syndrome, well‐known to induce cardiometabolic complications. We previously demonstrated that IH induces hyperinsulinemia and associated altered insulin signaling in adipose tissue, liver, and skeletal muscle, but impact of IH on cardiac insulin signaling and functional/structural consequences remains unknown. Therefore, the aims of this study were to investigate in both lean and obese mice the effects of chronic IH on the following: (1) cardiac insulin signaling and (2) cardiac remodeling and function.MethodsC57BL/6 J male mice were fed low‐fat (LFD) or high‐fat (HFD) diet for 20 weeks, and exposed to IH (21–5% FiO2, 60 s cycle, 8 h/day) or normoxia (N) for the last 6 weeks. Systemic insulin sensitivity was evaluated by an insulin tolerance test. Cardiac remodeling and contractile function were assessed by cardiac ultrasonography. Ultimately, hearts were withdrawn for biochemical and histological analysis.ResultsIn LFD mice, IH‐induced hyperinsulinemia and systemic insulin resistance that were associated with increased phosphorylations of cardiac insulin receptor and Akt on Tyr1150 and Ser473 residues, respectively. In addition, IH significantly increased cardiac interstitial fibrosis and cardiac contractility. In the HFD group, IH did not exert any additional effect, nor on insulin/Akt signaling, nor on cardiac remodeling and function.ConclusionOur study suggests that, despite systemic insulin resistance, IH exposure mediates an adaptive cardiac response in lean but not in obese mice. Further studies are needed to investigate which specific mechanisms are involved and to determine the long‐term evolution of cardiac responses to IH.

Serotonergic innervation of respiratory motor nuclei after cervical spinal injury: Impact of intermittent hypoxia

Although cervical spinal cord injury (cSCI) disrupts bulbo-spinal serotonergic projections, partial recovery of spinal serotonergic innervation below the injury site is observed after incomplete cSCI. Since serotonin contributes to functional recovery post-injury, treatments to restore or accelerate serotonergic reinnervation are of considerable interest. Intermittent hypoxia (IH) was reported to increase serotonin innervation near respiratory motor neurons in spinal intact rats, and to improve function after cSCI. Here, we tested the hypotheses that spontaneous serotonergic reinnervation of key respiratory (phrenic and intercostal) motor nuclei: 1) is partially restored 12 weeks post C2 hemisection (C2Hx); 2) is enhanced by IH; and 3) results from sprouting of spared crossed-spinal serotonergic projections below the site of injury. Serotonin was assessed via immunofluorescence in male Sprague Dawley rats with and without C2Hx (12 wks post-injury); individual groups were exposed to 28 days of: 1) normoxia; 2) daily acute IH (dAIH28: 10, 5 min 10.5% O2 episodes per day; 5 min normoxic intervals); 3) mild chronic IH (IH28-5/5: 5 min 10.5% O2 episodes; 5 min intervals; 8 h/day); or 4) moderate chronic IH (IH28-2/2: 2 min 10.5% O2 episodes; 2 min intervals; 8 h/day), simulating IH experienced during moderate sleep apnea. After C2Hx, the number of ipsilateral serotonergic structures was decreased in both motor nuclei, regardless of IH protocol. However, serotonergic structures were larger after C2Hx in both motor nuclei, and total serotonin immunolabeling area was increased in the phrenic motor nucleus but reduced in the intercostal motor nucleus. Both chronic IH protocols increased serotonin structure size and total area in the phrenic motor nuclei of uninjured rats, but had no detectable effects after C2Hx. Although the functional implications of fewer but larger serotonergic structures are unclear, we confirm that serotonergic reinnervation is substantial following injury, but IH does not affect the extent of reinnervation.

Intrahepatic Expression of Fatty Acid Translocase CD36 Is Increased in Obstructive Sleep Apnea.

Nocturnal intermittent hypoxia (IH) featuring obstructive sleep apnea (OSA) dysregulates hepatic lipid metabolism and might contribute to the development of non-alcoholic fatty liver disease (NAFLD) observed in OSA patients. However, further research is required to better understanding the molecular mechanisms underlying IH-induced hepatic lipid accumulation. Therefore, the aim of the present study was to determine the effects of OSA on hepatic CD36 expression and the impact of IH by using a mouse model of OSA. Histological analysis, lipid content and CD36 expression were assessed in livers from subjects who underwent liver biopsy and polygraphic study during sleep, and in livers from mice submitted to chronic IH mimicking OSA. Among those who presented OSA features, NAFLD were significantly more frequent than in control subjects with normal respiratory function (77.8 vs. 36.4%, respectively), and showed more severe liver disease. Interestingly, CD36 expression was significantly overexpressed within the liver of OSA patients with respect to controls, and a significant positive correlation was observed between hepatic levels of CD36 and the values of two well-known respiratory parameters that characterized OSA: apnea/hypopnea index (AHI) and oxygen desaturation index (ODI). Moreover, hepatic lipid accumulation as well as induction of hepatic lipogenic genes, and CD36 mRNA and protein expression were significantly higher in livers from mice exposed to IH conditions for 8 weeks than in their corresponding littermates. This study provides novel evidence that IH featuring OSA could contribute to NAFLD setup partly by upregulating hepatic CD36 expression.

Does the broad nature of sympathetic discharge affect our understanding regarding the impact of intermittent hypoxia on neurovascular transduction?

Does the broad nature of sympathetic discharge affect our understanding regarding the impact of intermittent hypoxia on neurovascular transduction?

Recovery of Serotonergic Innervation in Spinal Motor Nuclei below Cervical Spinal Injury: Effects of Intermittent Hypoxia

Cervical spinal cord injury (cSCI) disrupts serotonergic innervation below the injury. Since serotonin underlies motor functional recovery following cSCI, it is important to know the extent of serotonergic reinnervation after incomplete cSCI and to understand factors that accelerate that process. Repetitive acute intermittent hypoxia (rAIH) is one treatment known to elicit serotonin‐dependent respiratory and limb motor plasticity, partially restoring breathing and limb functions after chronic cSCI. Chronic intermittent hypoxia (CIH) similar to that experienced during sleep apnea elicits neuropathology, and potentially undermines the capacity for AIH‐induced motor plasticity. Although rAIH was previously reported to increase serotonergic innervation of the phrenic motor nucleus in intact rats, the impact of different intermittent hypoxia (IH) protocols on serotonergic innervation of respiratory motor nuclei in rats with or without chronic cSCI has not been investigated. Further, the impact of IH on serotonergic innervation of non‐respiratory motor nuclei has never been investigated. Thus, we tested the hypotheses that rAIH and CIH exert differential effects on serotonergic innervation of phrenic, intercostal, forelimb and axial motor nuclei motor nuclei post‐cSCI. Serotonergic innervation was assessed via immunofluorescence in male Sprague Dawley rats with and without C2 spinal hemisection (C2Hx; 12 wks post‐injury) exposed to 28 days of: 1) normoxia; 2) daily AIH (10, 5min 10.5% O2 episodes per day; 5min normoxic intervals); 3) mild CIH (5‐min 10.5% O2 episodes; 5min intervals; 8 hrs/day); and 4) moderate CIH (2min 10.5% O2 episodes; 2min intervals; 8 hrs/day). Rats received intrapleural injections of Cholera toxin B subunit 14 days before C2Hx to label phrenic and intercostal motor neurons. Forelimb and axial motor nuclei regions were determined using anatomical landmarks. In all regions investigated, no IH protocol impacted serotonergic innervation in intact or injured rats, contrary to previous reports. All areas had significant reductions in the number of serotonergic structures ipsilateral to C2Hx (p&lt;0.001). Serotonergic structures innervating ipsilateral phrenic nuclei were larger (p&lt;0.001), resulting in an overall increase in total innervation (p&lt;0.001). Serotonergic structures innervating ipsilateral intercostal nuclei were also larger (p&lt;0.001), but total innervation was reduced (p&lt;0.001) due to larger reductions in number. In forelimb and axial nuclei, the size of serotonergic structures was unaffected by C2Hx (p&lt;0.001), resulting in less total innervation ipsilateral to C2Hx (p&lt;0.0001). Thus, C2Hx deferentially impacts serotonin reinnervation in spinal motor nuclei ipsilateral to C2Hx. The functional impact of increased serotonergic structure size in phrenic and intercostal motor nuclei is unclear. Our results indicate substantial serotonergic reinnervation below cSCI at this time point, potentially enabling serotonin‐dependent, AIH‐induced plasticity with chronic cSCI.Support or Funding InformationSPARC OT2OD023854 NIH T32 HD043730 NIH K12 HD055929 and UF McKnight Brain Institute

Impact of Intermittent Hypoxia on Peripheral Nervous Systems in Obstructive Sleep Apnea Syndrome

Objectives: Intermittent hypoxia resulting in endothelial dysfunction in microvascular circulation constitutes one of the mechanisms underlying complications of obstructive sleep apnea syndrome (OSAS), such as hypertension and atherosclerosis. The role of intermittent hypoxia on peripheral nerves, however, is still debated. Here, we designed a study in patients with OSAS to investigate different levels of the central and peripheral nervous systems, in order to delineate what kind of pathologic substrate was present, if any, and at which level of the neuromuscular pathway. Methods: A total of 20 patients with OSAS and 18 sex- and age-matched healthy controls were enrolled in our study. All participants underwent nerve conduction studies (NCSs) to analyze peripheral nerves, evoked potentials for somatosensory, visual evoked potential (VEP) and brainstem auditory pathways, blink reflex studies to analyze brainstem and subcortical structures, and transcranial magnetic stimulation to analyze the motor cortex and corticospinal pathway. Results: A comparison of NCSs between the two groups showed that the motor amplitudes of the ulnar nerve (P = 0.015) and sensory amplitudes of the sural nerve (P = 0.026) were significantly smaller in the OSAS group than those in the control group. The mean P100 amplitudes of VEP responses were 7.11 ± 2.73 μV in the OSAS group and 9.75 ± 3.52 μV in the control group (P = 0.022). In correlation analysis, the amplitude of P100 responses was positively correlated with the lowest oxygen saturation (P = 0.026). Conclusion: Our results confirmed the presence of generalized axonal involvement in the peripheral nervous system in OSAS, probably secondary to chronic intermittent hypoxemia.

Impact of Intermittent Hypoxia on Sepsis Outcomes in a Murine Model

Sleep apnea has been associated with a variety of diseases, but its impact on sepsis outcome remains unclear. This study investigated the effect of intermittent hypoxia [IH]–the principal feature of sleep apnea–on murine sepsis. 5-week-old male C57BL6 mice were assigned to groups receiving severe IH (O2 fluctuating from room air to an O2 nadir of 5.7% with a cycle length of 90 seconds), mild IH (room air to 12%, 4 minutes/cycle), or room air for 3 weeks. Sepsis was induced by cecal ligation and puncture and survival was monitored. Sepsis severity was evaluated by murine sepsis scores, blood bacterial load, plasma tumor necrosis factor-α [TNF-α]/interleukin-6 [IL-6] levels and histopathology of vital organs. Compared with normoxic controls, mice subjected to severe IH had earlier mortality, a lower leukocyte count, higher blood bacterial load, higher plasma TNF-α and IL-6 levels, more severe inflammatory changes in the lung, spleen and small intestine. Mice subjected to mild IH did not differ from normoxic controls, except a higher IL-6 level after sepsis induced. The adverse impact of severe IH was reversed following a 10-day normoxic recovery. In conclusion, severe IH, not mild IH, contributed to poorer outcomes in a murine sepsis model.

Hippocampal neural stem cells undergo fate switch following intermittent hypoxia

Adult neurogenesis is a phenomenon widely recognized as a process supporting neurophysiology of the hippocampus. We recently reported that 30 days of intermittent hypoxia (IH), a principal consequence for sleep apnea, stimulates the expansion of hippocampal neural stem cells (NSCs), yet suppresses the generation of adult‐born neurons. This study investigates how IH impacts NSCs by using a shorter duration of IH. We hypothesize that 10 days of IH (IH10) redirects the course of development of NSCs. We examined how NSCs in the neurogenic niche of the dentate gyrus are affected by IH10. Immunohistochemical analysis revealed that the number of NSCs (Sox2+ cells) was not increased following IH10, yet appears to increase in quiescent NSCs (i.e., Sox2+ cells that co‐express the astrocytic marker, S100b, and do not develop into adult‐born neurons). Fewer NSCs were observed transitioning into intermediate neuronal progenitors (INPs, SOX2+/TBR2+ cells) and a reduction in the total number of INPs (TBR2+ cells) was also noted. These experiments suggest that the impact of IH on cells involved with adult neurogenesis is cell‐type specific. Our findings provide further support that untreated sleep apnea may impact the fate of pluripotent cellular constituents in the central nervous system.Support or Funding InformationThis work was supported by NIH R01 NS10742101 (AJG)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Renal cortical oxygen tension is decreased following exposure to long-term but not short-term intermittent hypoxia in the rat.

Chronic kidney disease (CKD) occurs in more than 50% of patients with obstructive sleep apnea (OSA). However, the impact of intermittent hypoxia (IH) on renal function and oxygen homeostasis is unclear. Male Sprague-Dawley rats were exposed to IH (270 s at 21% O2; 90 s hypoxia, 6.5% O2 at nadir) for 4 h [acute IH (AIH)] or to chronic IH (CIH) for 8 h/day for 2 wk. Animals were anesthetized and surgically prepared for the measurement of mean arterial pressure (MAP), and left renal excretory function, renal blood flow (RBF), and renal oxygen tension (Po2). AIH had no effect on MAP (123 ± 14 vs. 129 ± 14 mmHg, means ± SE, sham vs. IH). The CIH group was hypertensive (122 ± 9 vs. 144 ± 15 mmHg, P < 0.05). Glomerular filtration rate (GFR) (0.92 ± 0.27 vs. 1.33 ± 0.33 ml/min), RBF (3.8 ± 1.5 vs. 7.2 ± 2.4 ml/min), and transported sodium (TNa) (132 ± 39 vs. 201 ± 47 μmol/min) were increased in the AIH group (all P < 0.05). In the CIH group, GFR (1.25 ± 0.28 vs. 0.86 ± 0.28 ml/min, P < 0.05) and TNa (160 ± 39 vs. 120 ± 40 μmol/min, P < 0.05) were decreased, while RBF (4.13 ± 1.5 vs. 3.08 ± 1.5 ml/min) was not significantly different. Oxygen consumption (QO2) was increased in the AIH group (6.76 ± 2.60 vs. 13.60 ± 7.77 μmol/min, P < 0.05), but it was not significantly altered in the CIH group (3.97 ± 2.63 vs. 6.82 ± 3.29 μmol/min). Cortical Po2 was not significantly different in the AIH group (46 ± 4 vs. 46 ± 3 mmHg), but it was decreased in the CIH group (44 ± 5 mmHg vs. 38 ± 2 mmHg, P < 0.05). For AIH, renal oxygen homeostasis was preserved through a maintained balance between O2 supply (RBF) and consumption (GFR). For CIH, mismatched TNa and QO2 reflect inefficient O2 utilization and, thereby, sustained decrease in cortical Po2.

Mechanisms involved in the deleterious impact of intermittent hypoxia on ischemic cardiomyopathy

Chronic intermittent hypoxia (IH) is the hallmark feature of sleep-disordered breathing and clinical studies underlie a poor prognosis in severe apneic patients post-myocardial infarction (MI). Thus, it is necessary to understand specific mechanistic pathways involved in this post-MI aggravation, in order to improve the management of patient. Previous studies showed that IH activates myocardial HIF1-endoplasmic reticulum (ER) stress axis. Thus, we aimed at highlighting: 1 the impact of IH on the development of ischemic cardiomyopathy; 2 to determine the involved mechanisms, in particular the role of IH on HIF1-ER stress axis, sympathetic activation and calcium (Ca 2+ ) homeostasis perturbations. MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Then, rats were exposed to IH (21–5% FiO 2 , 60 s cycle, 8 h/day) or normoxia (N) for 1 to 12 weeks. Cardiac function was evaluated by ultrasonography and cardiac catheterization. Ultimately, hearts were withdrawn for biochemical and histological analysis, as well as Ca 2+ transient imaging after cardiomyocytes isolation. We observed more important alterations in ejection fraction, dP/dtmax, and dP/dtmin in IH rats compared to N. These IH rats exhibited sympathetic hyperactivation (i.e. increased LF/HF ratio and adrenal gland hypertrophy), which was associated with an increased HIF1 expression post-MI. Expressions of GRP78, CHOP and caspase 12 proteins were also increased by IH, suggesting a pro apoptotic ER stress. Except from phospholamban that was hyper-phosphorylated, Ca 2+ handling protein expressions were not different between N and IH. Finally, Ca 2+ transient analysis is ongoing. As in severe apneic patients, we showed that IH is deleterious on ischemic cardiomyopathy development. Besides, HIF1, sympathetic activity, ER stress and Ca 2+ homeostasis are disturbed. Further studies are needed to better understand the relationship between these mechanisms.

Impact of intermittent hypoxia on cardiovascular remodeling in a murine model of sleep apnea: effect of age

Impact of intermittent hypoxia on cardiovascular remodeling in a murine model of sleep apnea: effect of age

Impact of intermittent hypoxia and exercise on blood pressure and metabolic features from obese subjects suffering sleep apnea-hypopnea syndrome.

Strategies designed to reduce adiposity and cardiovascular-accompanying manifestations have been based on nutritional interventions conjointly with physical activity programs. The aim of this 13-week study was to investigate the putative benefits associated to hypoxia plus exercise on weight loss and relevant metabolic and cardiorespiratory variables, when prescribed to obese subjects with sleep apnea syndrome following dietary advice. The participants were randomly distributed in the following three groups: control, normoxia, and hypoxia. All the subjects received dietary advice while, additionally, normoxia group was trained under normal oxygen concentration and Hypoxia group under hypoxic conditions. There was a statistically significant decrease in fat-free mass (Kg) and water (%) on the control compared to normoxia group (p < 0.05 and p < 0.01, respectively). Body weight, body mass index, and waist circumference decreased in all the groups after the study. Moreover, leukocyte count was increased after the intervention in hypoxia compared to control group (p < 0.05). There were no statistically significant variations within groups in other variables, although changes in appetite were found after the 13-week period. In addition, associations between the variations in the leukocyte count and fat mass have been found. The hypoxia group showed some specific benefits concerning appetite and cardiometabolic-related measurements as exertion time and diastolic blood pressure, with a therapeutical potential.