Intermittent Hypoxia Alters Gene Expression in Peripheral Blood Mononuclear Cells (PBMC) of Healthy Volunteers
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE71356 | GEO | 2015/07/27
SECONDARY ACCESSION(S): PRJNA291025
REPOSITORIES: GEO
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Project description:Obstructive sleep apnea (OSA) leads to increased cardiovascular morbidity and mortality, which have been attributed to intermittent hypoxia (IH). The effects of IH on lung structure and function are unknown. We used a mouse model of chronic IH, which mimics the O2 profile in patients with OSA. We exposed adult C57BL/6J mice to 3 months of IH with an FIO2 nadir of 5%, 60 times/hr during the 12hr light phase. Control mice were exposed to room air.
2010-12-31 | GSE21409 | GEO
Project description:Obstructive sleep apnea (OSA) leads to increased cardiovascular morbidity and mortality, which have been attributed to intermittent hypoxia (IH). The effects of IH on lung structure and function are unknown. We used a mouse model of chronic IH, which mimics the O2 profile in patients with OSA. We exposed adult C57BL/6J mice to 3 months of IH with an FIO2 nadir of 5%, 60 times/hr during the 12hr light phase. Control mice were exposed to room air. Gene microarrays were performed in a separate subset of animals (IH, n = 5; control, n = 5). Total RNA was isolated from lung tissue using the Trizol Reagent method, gene microarrays were performed with the Affymetrix GeneChip® Mouse Genome 430A 2.0 Array (MG 430A 2.0; Affymetrix, Inc., Santa Clara, CA) and analyzed using Significance Analysis of Microarray (SAM) software.
2010-12-31 | E-GEOD-21409 | biostudies-arrayexpress
Project description:Obstructive Sleep Apnea (OSA) engenders repetitive desaturation-reoxygenation sequences called intermittent hypoxia (IH), now widely accepted as an independent risk factor for the occurrence and progression of non-alcoholic fatty liver disease (NAFLD). The specific molecular mechanisms linking IH and the development and progression of NAFLD remain elusive. NAFLD pathogenesis is multifactorial including immune cell-driven inflammation as a key mechanism in the transition from fatty liver to steatohepatitis (NASH). The overall goal of this study was to identify the specific impact of IH on liver inflammation in the absence of major confounders frequently encountered in OSA clinical research (i.e., obesity, diabetes, reduced physical activity). We employed a model of lean mice exposed to long-term IH (16 weeks) and a cohort of lean OSA patients free of comorbidities (n=71) coupled with high-throughput hepatic transcriptomics, lipidomics and targeted serum proteomics. For the first time, we have demonstrated that long-term IH is an independent “hit” sufficient by itself to induce the NASH molecular signatures found in human steatohepatitis transcriptomic datasets.We identified a unique set of biomarkers in mice and humans (PPARs, NRFs, arachidonic acid, IL16, IL20, IFNB and TNFa) associated with early hepatic and systemic inflammation. This molecular connection between IH, sleep apnea and steatohepatitis warrants further investigation in clinical trials and support the systematic implementation of sleep apnea diagnosis in liver disease phenotyping. Our original signatures could allow the identification of potential diagnostic and treatment response markers, as well as therapeutic targets in the comorbid association between NAFLD and OSA.
2024-02-14 | GSE242668 | GEO
Project description:The long-term effects of neonatal intermittent hypoxia (IH), an accepted model of apnea-induced hypoxia, are unclear. We have previously shown lasting âprogrammingâ effects on the HPA axis in adult rats exposed to neonatal IH. We hypothesized that neonatal rat exposure to IH will subsequently result in a heightened inflammatory state in the adult. Rat pups were exposed to normoxia (control) or six cycles of 5% IH or 10% IH over one hour daily from postnatal day 2 â 6. Plasma samples from blood obtained at 114 days of age were analyzed by assessing the capacity to induce transcription in a healthy peripheral blood mononuclear cell (PBMC) population and read using a high-density microarray. The analysis of plasma from adult rats previously exposed to neonatal 5% IH vs. 10% IH resulted in 2,579 significantly regulated genes including increased expression of Cxcl1, Cxcl2, Ccl3, Il1a, and Il1b. We conclude that neonatal exposure to intermittent hypoxia elicits a long-lasting programming effect in the adult resulting in an upregulation of inflammatory-related genes. Apnea is the most common cause of neonatal hypoxia affecting about 50% of preterm births (30 â 31 weeks), usually due to immature respiratory development. Upregulation of inflammatory genes and pathways in children 7 â 10 years of age has been shown, and there is a known increased risk of insulin resistance in adulthood when the fetus is exposed to maternal hypoxia, but the mechanism is unclear. The long-term metabolic, endocrine, and immunological effects of neonatal intermittent hypoxia (IH) exposure, an accepted model of apnea-induced hypoxia, have not been thoroughly evaluated. Recent studies in rats have shown that perinatal IH exposure can result in oxidative stress, causing a permanent immune response subsequently resulting in features of diabetes mellitus. We have previously examined adult rats exposed to neonatal intermittent hypoxia and perinatal continuous hypoxia, and have found lasting âÂÂprogrammingâ effects on the HPA axis. We now assess the long term effects of an accepted model of apnea-induced hypoxia using a validated transcriptional bioassay to study the extracellular milieu of adult rats exposed to neonatal intermittent hypoxia. We hypothesize that exposure to neonatal intermittent hypoxia will result in an increased inflammatory state in the adult as a result of long-lasting programming. Sprague-Dawley (SD) rat pups were treated with neonatal normoxia (21% O2, control), 5% intermittent hypoxia (IH), or 10% IH on postnatal days (PD) 2-6, daily over 1 hr. They were reared normally by birth dams and weaned at PD22. Males were allowed to mature and sacrificed at age PD114 after an overnight fast. Whole blood collected by decapitation into tubes with EDTA, and plasma saved for further analysis. Two adult (~180 day) male Brown Norway (BN) rats served as PBMC donors. Cells were incubated with 20% plasma that was either autologous BN (self-control), or one of 3 pools: a) SD normoxic N=8, b) SD 5% IH treated N=5, and c) SD 10% IH N=3.
2016-01-07 | E-GEOD-74145 | biostudies-arrayexpress
Project description:The long-term effects of neonatal intermittent hypoxia (IH), an accepted model of apnea-induced hypoxia, are unclear. We have previously shown lasting “programming” effects on the HPA axis in adult rats exposed to neonatal IH. We hypothesized that neonatal rat exposure to IH will subsequently result in a heightened inflammatory state in the adult. Rat pups were exposed to normoxia (control) or six cycles of 5% IH or 10% IH over one hour daily from postnatal day 2 – 6. Plasma samples from blood obtained at 114 days of age were analyzed by assessing the capacity to induce transcription in a healthy peripheral blood mononuclear cell (PBMC) population and read using a high-density microarray. The analysis of plasma from adult rats previously exposed to neonatal 5% IH vs. 10% IH resulted in 2,579 significantly regulated genes including increased expression of Cxcl1, Cxcl2, Ccl3, Il1a, and Il1b. We conclude that neonatal exposure to intermittent hypoxia elicits a long-lasting programming effect in the adult resulting in an upregulation of inflammatory-related genes. Apnea is the most common cause of neonatal hypoxia affecting about 50% of preterm births (30 – 31 weeks), usually due to immature respiratory development. Upregulation of inflammatory genes and pathways in children 7 – 10 years of age has been shown, and there is a known increased risk of insulin resistance in adulthood when the fetus is exposed to maternal hypoxia, but the mechanism is unclear. The long-term metabolic, endocrine, and immunological effects of neonatal intermittent hypoxia (IH) exposure, an accepted model of apnea-induced hypoxia, have not been thoroughly evaluated. Recent studies in rats have shown that perinatal IH exposure can result in oxidative stress, causing a permanent immune response subsequently resulting in features of diabetes mellitus. We have previously examined adult rats exposed to neonatal intermittent hypoxia and perinatal continuous hypoxia, and have found lasting “programming” effects on the HPA axis. We now assess the long term effects of an accepted model of apnea-induced hypoxia using a validated transcriptional bioassay to study the extracellular milieu of adult rats exposed to neonatal intermittent hypoxia. We hypothesize that exposure to neonatal intermittent hypoxia will result in an increased inflammatory state in the adult as a result of long-lasting programming.
2016-01-07 | GSE74145 | GEO
Project description:Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia (IH) and is associated with a host of health complications. Although the lung is the first organ to sense changes in oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor- (HIF)-responsive pathways. We hypothesized that exposure to IH would lead to cell-specific up and downregulation of diverse expression pathways. We identified changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells showed the most prominent transcriptional changes. Upregulated genes in myofibroblast cells were enriched for genes associated with pulmonary hypertension and included targets of several drugs currently used to treat chronic pulmonary diseases. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.
2021-02-18 | GSE145434 | GEO
Project description:Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia (IH) and is associated with a host of health complications. Although the lung is the first organ to sense changes in oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor- (HIF)-responsive pathways. We hypothesized that exposure to IH would lead to cell-specific up and downregulation of diverse expression pathways. We identified changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells showed the most prominent transcriptional changes. Upregulated genes in myofibroblast cells were enriched for genes associated with pulmonary hypertension and included targets of several drugs currently used to treat chronic pulmonary diseases. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.
2021-02-18 | GSE145435 | GEO
Project description:Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA), which has been proposed as the major determinant of processes involving tumor invasion and metastasis. To study whether circulating DNA (cirDNA) in blood plasma reflects the changes that the tumor cells undergo under IH conditions, we used a xenografted murine model. Mice engrafted with TC1 epithelial lung and controls were exposed to IH or room air (RA) conditions. Plasma cirDNA amounts were significantly increased in mice exposed to IH (p<0.05). We found a significant correlation between plasma cirDNA concentration and tumor size, weight and invasiveness (p<0.05). Using a microarray-based approach, we identified 2,094 regions showing significant differential cirDNA modifications. System biology analysis revealed an association with molecular pathways misregulated in cancer progression and with distal and TSS-associated transcription factor binding sites. We detected clusters of highly variable regions in chromosomes 7, 13, 14 and X, which may highlight hotspots for DNA deletions. Single locus displayed high intragroup variation, suggesting cellular heterogeneity within the tissue may be associated to cirDNA release. Our result showed that exposure to IH increases the shedding of cirDNA into circulation, which carries epigenetic modifications that may characterize cell populations within the tumor that preferentially release their DNA upon IH exposure. 6 xenografted mouse samples were analyzed by microarray analysis: Mouse exposed to IH (n=3, XenoIH group) and mouse exposed to room air conditions (n=3, XenoRA group)
2015-02-24 | E-GEOD-61070 | biostudies-arrayexpress
Project description:Endothelial cell (EC) dysfunction precedes the development of cardiovascular disease in OSA; however, the mechanisms by which ECs respond to these hypoxic events is poorly understood. To better understand EC responses to hypoxia, we examined the effects of both sustained hypoxia (SH) and intermittent hypoxia (IH) on the activation of HIF-1α in Endothelial Cells (ECs). While SH stabilized HIF-1α and led to its nuclear localization, IH didn’t activate HIF-1α and its downsteram gene expression. Using RNA-sequencing, we evaluated transcriptional responses of ECs to hypoxia. SH induced expression of HIF-1α and hypoxia response genes, while IH affected cell-cycle regulation genes.
2024-11-01 | GSE279434 | GEO
Project description:Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA), which has been proposed as the major determinant of processes involving tumor invasion and metastasis. To study whether circulating DNA (cirDNA) in blood plasma reflects the changes that the tumor cells undergo under IH conditions, we used a xenografted murine model. Mice engrafted with TC1 epithelial lung and controls were exposed to IH or room air (RA) conditions. Plasma cirDNA amounts were significantly increased in mice exposed to IH (p<0.05). We found a significant correlation between plasma cirDNA concentration and tumor size, weight and invasiveness (p<0.05). Using a microarray-based approach, we identified 2,094 regions showing significant differential cirDNA modifications. System biology analysis revealed an association with molecular pathways misregulated in cancer progression and with distal and TSS-associated transcription factor binding sites. We detected clusters of highly variable regions in chromosomes 7, 13, 14 and X, which may highlight hotspots for DNA deletions. Single locus displayed high intragroup variation, suggesting cellular heterogeneity within the tissue may be associated to cirDNA release. Our result showed that exposure to IH increases the shedding of cirDNA into circulation, which carries epigenetic modifications that may characterize cell populations within the tumor that preferentially release their DNA upon IH exposure.
2015-02-24 | GSE61070 | GEO