scholarly journals Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Gang Wu ◽  
Yin Yeng Lee ◽  
Evelyn M Gulla ◽  
Andrew Potter ◽  
Joseph Kitzmiller ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Cell Types ◽  
Short Term Exposure ◽  
Obstructive Sleep ◽  
Chronic Pulmonary Diseases ◽  
Transcriptional Changes ◽  
Expression Pathways ◽  
Health Complications ◽  
Upregulated Genes

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-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.

scholarly journals Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease

2020 ◽  
Author(s):  
Gang Wu ◽  
Yin Yeng Lee ◽  
Evelyn M. Gulla ◽  
Andrew Potter ◽  
Joseph Kitzmiller ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Cell Types ◽  
Cellular Mechanisms ◽  
Multiple Systems ◽  
Short Term Exposure ◽  
Obstructive Sleep ◽  
Chronic Pulmonary Diseases ◽  
Expression Pathways ◽  
Health Complications

AbstractObstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia and is associated with a host of health complications including dementia, diabetes, heart failure, and stroke. Although the lung is the first organ to sense changes in inspired oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor (HIF)-responsive pathways. Furthermore, cellular mechanisms causing disease progression across multiple systems in OSA are unknown. We hypothesized that exposure to IH would lead to up- and down-regulation of diverse expression pathways and that individual cell populations would show distinctive responses to IH. We identify changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells show the most prominent transcriptional changes. Interestingly, up-regulated genes in endothelial, fibroblast, and myofibroblast cells were enriched for genes associated with pulmonary fibrosis and pulmonary hypertension. These genes include targets of several drugs currently used to treat chronic pulmonary diseases. Our results reveal potential candidates for cell-targeted therapy seeking to minimize pulmonary effects of OSA. 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.

scholarly journals Transcriptomic Changes of Murine Visceral Fat Exposed to Intermittent Hypoxia at Single Cell Resolution

2020 ◽  
Vol 22 (1) ◽  
pp. 261
Author(s):  
Abdelnaby Khalyfa ◽  
Wesley Warren ◽  
Jorge Andrade ◽  
Christopher A. Bottoms ◽  
Edward S. Rice ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Cell Types ◽  
Cellular Level ◽  
Cellular Heterogeneity ◽  
Transcriptional Networks ◽  
Metabolic Dysfunction ◽  
Rna Seq ◽  
Obstructive Sleep ◽  
Differential Expressed Gene ◽  
Key Aspects

Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA) and induces metabolic dysfunction manifesting as inflammation, increased lipolysis and insulin resistance in visceral white adipose tissues (vWAT). However, the cell types and their corresponding transcriptional pathways underlying these functional perturbations are unknown. Here, we applied single nucleus RNA sequencing (snRNA-seq) coupled with aggregate RNA-seq methods to evaluate the cellular heterogeneity in vWAT following IH exposures mimicking OSA. C57BL/6 male mice were exposed to IH and room air (RA) for 6 weeks, and nuclei from vWAT were isolated and processed for snRNA-seq followed by differential expressed gene (DEGs) analyses by cell type, along with gene ontology and canonical pathways enrichment tests of significance. IH induced significant transcriptional changes compared to RA across 14 different cell types identified in vWAT. We identified cell-specific signature markers, transcriptional networks, metabolic signaling pathways, and cellular subpopulation enrichment in vWAT. Globally, we also identify 298 common regulated genes across multiple cellular types that are associated with metabolic pathways. Deconvolution of cell types in vWAT using global RNA-seq revealed that distinct adipocytes appear to be differentially implicated in key aspects of metabolic dysfunction. Thus, the heterogeneity of vWAT and its response to IH at the cellular level provides important insights into the metabolic morbidity of OSA and may possibly translate into therapeutic targets.

scholarly journals Models of intermittent hypoxia and obstructive sleep apnea: molecular pathways and their contribution to cancer

2018 ◽  
Vol 315 (4) ◽  
pp. R669-R687 ◽  
Author(s):  
Imre Hunyor ◽  
Kristina M. Cook
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
Inflammatory Responses ◽  
Hypoxia Inducible Factor ◽  
Small Animal ◽  
Molecular Pathways ◽  
Significant Heterogeneity ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) is common and linked to a variety of poor health outcomes. A key modulator of this disease is nocturnal intermittent hypoxia. There is striking epidemiological evidence that patients with OSA have higher rates of cancer and cancer mortality. Small-animal models demonstrate an important role for systemic intermittent hypoxia in tumor growth and metastasis, yet the underlying mechanisms are poorly understood. Emerging data indicate that intermittent hypoxia activates the hypoxic response and inflammatory pathways in a manner distinct from chronic hypoxia. However, there is significant heterogeneity in published methods for modeling hypoxic conditions, which are often lacking in physiological relevance. This is particularly important for studying key transcriptional mediators of the hypoxic and inflammatory responses such as hypoxia-inducible factor (HIF) and NF-κB. The relationship between HIF, the molecular clock, and circadian rhythm may also contribute to cancer risk in OSA. Building accurate in vitro models of intermittent hypoxia reflective of OSA is challenging but necessary to better elucidate underlying molecular pathways.

scholarly journals An innovative intermittent hypoxia model for cell cultures allowing fast Po2 oscillations with minimal gas consumption

2017 ◽  
Vol 313 (4) ◽  
pp. C460-C468 ◽  
Author(s):  
Mélanie Minoves ◽  
Jessica Morand ◽  
Frédéric Perriot ◽  
Morgane Chatard ◽  
Brigitte Gonthier ◽  
...  
Keyword(s):  
Cell Culture ◽  
Cell Cultures ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Cellular Level ◽  
Cycle Duration ◽  
New Device ◽  
Functional Studies ◽  
Obstructive Sleep ◽  
Gas Consumption

Performing hypoxia-reoxygenation cycles in cell culture with a cycle duration accurately reflecting what occurs in obstructive sleep apnea (OSA) patients is a difficult but crucial technical challenge. Our goal was to develop a novel device to expose multiple cell culture dishes to intermittent hypoxia (IH) cycles relevant to OSA with limited gas consumption. With gas flows as low as 200 ml/min, our combination of plate holders with gas-permeable cultureware generates rapid normoxia-hypoxia cycles. Cycles alternating 1 min at 20% O2 followed by 1 min at 2% O2 resulted in Po2 values ranging from 124 to 44 mmHg. Extending hypoxic and normoxic phases to 10 min allowed Po2 variations from 120 to 25 mmHg. The volume of culture medium or the presence of cells only modestly affected the Po2 variations. In contrast, the nadir of the hypoxia phase increased when measured at different heights above the membrane. We validated the physiological relevance of this model by showing that hypoxia inducible factor-1α expression was significantly increased by IH exposure in human aortic endothelial cells, murine breast carcinoma (4T1) cells as well as in a blood-brain barrier model (2.5-, 1.5-, and 6-fold increases, respectively). In conclusion, we have established a new device to perform rapid intermittent hypoxia cycles in cell cultures, with minimal gas consumption and the possibility to expose several culture dishes simultaneously. This device will allow functional studies of the consequences of IH and deciphering of the molecular biology of IH at the cellular level using oxygen cycles that are clinically relevant to OSA.

scholarly journals Urine 5-Eicosatetraenoic Acids as Diagnostic Markers for Obstructive Sleep Apnea

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1242
Author(s):  
Hyun-Woo Shin ◽  
Kumsun Cho ◽  
Chae-Seo Rhee ◽  
Il-Hee Hong ◽  
Seok Hyun Cho ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
Mononuclear Cells ◽  
Hypoxia Inducible Factor ◽  
Apnea Hypopnea Index ◽  
Hypoxia Inducible Factor 1 ◽  
Human Mononuclear Cells ◽  
Obstructive Sleep ◽  
Arachidonic Acid Derivatives

Early detection of obstructive sleep apnea (OSA) is needed to reduce cardiovascular sequelae and mortality. Full-night polysomnography has been used for diagnosing OSA, but it is too expensive and inconvenient for patients to handle. Metabolome-wide analyses were performed to find and validate surrogate markers for OSA. We further investigated the mechanism underlying hypoxic induction of the markers in human cells and mice. Arachidonic acid derivatives 5-HETE and 5-oxoETE were detected in urine samples. The levels (mean ± SD, ng per mg creatinine) of 5-HETE and 5-oxoETE were 56.4 ± 26.2 and 46.9 ± 18.4 in OSA patients, respectively, which were significantly higher than those in controls (22.5 ± 4.6 and 18.7 ± 3.6). Both levels correlated with the apnea-hypopnea index and the lowest oxygen saturation on polysomnography. After the treatment with the continuous positive airway pressure, the metabolite levels were significantly reduced compared with those before the treatment. In human mononuclear cells subjected to intermittent hypoxia, 5-HETE and 5-oxoETE productions were induced by hypoxia-inducible factor 1 and glutathione peroxidase. When mice were exposed to intermittent hypoxia, 5-HETE and 5-oxoETE were excreted more in urine. They were identified and verified as new OSA markers reflecting hypoxic stress. The OSA markers could be used for OSA diagnosis and therapeutic evaluation.

scholarly journals Endothelin-1 mediates intermittent hypoxia-induced inflammatory vascular remodeling through HIF-1 activation

2016 ◽  
Vol 120 (4) ◽  
pp. 437-443 ◽  
Author(s):  
Emmanuelle Gras ◽  
Elise Belaidi ◽  
Anne Briançon-Marjollet ◽  
Jean-Louis Pépin ◽  
Claire Arnaud ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Intima Media Thickness ◽  
Nuclear Factor Κb ◽  
Endothelin Receptor ◽  
Wild Type ◽  
Endothelin 1 ◽  
Hypoxia Inducible Factor 1 ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) is a major risk factor for cardiovascular mortality, and apnea-induced intermittent hypoxia (IH) is known to promote various cardiovascular alterations such as vascular remodeling. However, the mechanisms that underlie IH remain incompletely investigated. We previously demonstrated that the hypoxia-inducible factor-1 (HIF-1) and endothelin-1 (ET-1) are involved in arterial hypertension and myocardial susceptibility to infarction induced by IH. Thus the objective of the present study was to investigate whether both ET-1 and HIF-1 were also involved in the vascular inflammatory remodeling induced by IH. Mice partially deficient for the Hif1α gene (HIF-1α+/−) and their wild-type equivalents, as well as C57BL/6J mice, treated or not with bosentan, a dual endothelin receptor antagonist, were exposed to IH or normoxia for 2 wk, 8 h/day. Splenocyte proliferative and secretory capacities, aortic nuclear factor-κB (NF-κB) and HIF-1 activities, and expression of cytokines and intima-media thickness (IMT) were measured. IH induced a systemic and aortic inflammation characterized by an increase in splenocyte proliferative and secretory capacities, aortic NF-κB activity, and cytokine expression in the aortic wall. This was accompanied by an increase in IMT. These modifications were prevented in HIF-1α+/− and bosentan-treated mice. The results of this study suggest that ET-1 is a major contributor to the vascular inflammatory remodeling induced by OSA-related IH, probably through HIF-1-dependent activation of NF-κB.

scholarly journals Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3888
Author(s):  
Elena Díaz-García ◽  
Sara García-Tovar ◽  
Raquel Casitas ◽  
Ana Jaureguizar ◽  
Ester Zamarrón ◽  
...  
Keyword(s):  
Sleep Apnea ◽  
Intracellular Signaling ◽  
Intermittent Hypoxia ◽  
Epithelial To Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Matrix Metalloproteinase 2 ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Obstructive Sleep ◽  
Cancer Aggressiveness

As some evidence suggests that hypoxia might be an inducer of nuclear paraspeckle formation, we explore whether intermittent hypoxia (IH)-mediated paraspeckle protein-1 (PSPC1) overexpression might contribute to the activation of tumor growth factor (TGF)β-SMAD pathway in patients with obstructive sleep apnea (OSA). This activation would promote changes in intracellular signaling that would explain the increased cancer aggressiveness reported in these patients. Here, we show that patients with OSA exhibit elevated PSPC1 levels both in plasma and in monocytes. Our data suggest that PSPC1 is ultimately delivered to the plasma through its cleavage from OSA monocytes by matrix metalloproteinase-2 (MMP2). In addition, IH promotes PSPC1, TGFβ, and MMP2 expression in monocytes through the hypoxia-inducible factor. Lastly, both PSPC1 and TGFβ induce increased expression of genes that drive the epithelial-to-mesenchymal transition. Our study details the mechanism by which hypoxemia upmodulates the extracellular release of PSPC1 by means of MMP2, such that plasma PSPC1 together with TGFβ activation signaling further promotes tumor metastasis and supports cancer aggressiveness in patients with OSA.

scholarly journals Hypoxia-inducible factor-1 mediates pancreatic β-cell dysfunction by intermittent hypoxia

2020 ◽  
Vol 319 (5) ◽  
pp. C922-C932
Author(s):  
Ning Wang ◽  
Xue-Feng Shi ◽  
Shakil A. Khan ◽  
Benjamin Wang ◽  
Gregg L. Semenza ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Basal Insulin ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Min6 Cells ◽  
Cell Dysfunction ◽  
Obstructive Sleep ◽  
Basal Insulin Secretion

The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-cell-specific HIF-1−/− mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic β-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in β-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1α HET mice as well as in β-HIF-1−/− mice. IH-evoked β-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression, and these effects were abolished with genetic silencing of HIF-1α. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2O2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2O2 contribute to IH-induced pancreatic β-cell dysfunction.

Lysine demethylase KDM6B regulates HIF-1α mediated systemic and cellular responses to intermittent hypoxia

2021 ◽  
Author(s):  
Jayasri Nanduri ◽  
Ning Wang ◽  
Benjamin L Wang ◽  
Nanduri R. Prabhakar
Keyword(s):  
Transcriptional Activation ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Plasma Catecholamines ◽  
Gene Promoter ◽  
Independent Manner ◽  
Obstructive Sleep ◽  
Induced Hypertension ◽  
Responsive Element ◽  
Lysine Demethylase

Intermittent hypoxia (IH) is a hallmark manifestation of Obstructive Sleep Apnea (OSA). Rodents treated with IH exhibit hypertension. Hypoxia-inducible factor (HIF)-1-dependent transcriptional activation of NADPH oxidases (Nox) and the resulting increase in reactive oxygen species (ROS) levels is a major molecular mechanism underlying IH/OSA-induced hypertension. Jumanji C (JmjC)-containing histone lysine demethylases (JmjC-KDMs) are coactivators of HIF-1-dependent transcriptional activation. In the present study, we tested the hypothesis that JmjC-KDMs are required for IH-evoked HIF-1 transcriptional activation of Nox4 and the ensuing hypertension. Studies were performed on pheochromocytoma (PC)12 cells and rats. IH increased KDM6B protein and enzyme activity in PC12 cells in a HIF-1-independent manner as evidenced by unaltered KDM6B activation by IH in HIF-1α shRNA treated cells. Cells treated with IH showed increased HIF-1-dependent Nox4 transcription as indicated by increased HIF-1α binding to hypoxia responsive element (HRE) sequence of the Nox4 gene promoter demonstrated by chromatin immunoprecipitation (ChiP) assay. Pharmacological blockade of KDM6B with GSKJ4, a specific KDM6 inhibitor, or genetic silencing of KDM6B with shRNA abolished IH-induced Nox4 transcriptional activation by blocking HIF-1α binding to the promoter of the NOX4 gene. Treating IH exposed rats with GSKJ4 showed: a) absence of KDM6B activation and HIF-1-dependent Nox4 transcription in the adrenal medullae, as well as b) absence of elevated plasma catecholamines and hypertension. Collectively, these findings indicate that KDM6B functions as a coactivator of HIF-1-mediated Nox4 transactivation and demonstrate a hitherto uncharacterized role for KDM's in IH-induced hypertension by HIF-1.

scholarly journals Extracellular vesicles derived from lung cancer cells exposed to intermittent hypoxia upregulate programmed death ligand 1 expression in macrophages

2021 ◽  
Author(s):  
Yuanling Liu ◽  
Minzhen Lu ◽  
Jianan Chen ◽  
Siqi Li ◽  
Yiyu Deng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Intermittent Hypoxia ◽  
Immune Surveillance ◽  
Hypoxia Inducible Factor ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Obstructive Sleep ◽  
Nsclc Patients

Abstract Purpose Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), compromises immune surveillance through the upregulation of programmed cell death-1 ligand (PD-L1). Tumor-released extracellular vesicles (EVs) have been reported to modulate immunosuppressive activities. We investigated whether or not EVs derived from intermittent hypoxic lung cancer cells can alter the expression of PD-L1 in macrophages. Methods The expression of PD-L1+monocytes from 40 patients with newly diagnosed non-small-cell lung cancer (NSCLC) and with (n=21) or without (n=19) OSA were detected. Plasma EVs isolated from NSCLC patients with moderate–severe OSA (n=4) and without OSA (n=4) were co-cultured with macrophages. A549 cells were exposed to normoxia or IH (48 cycles of 5 min of 1% O2 hypoxia, followed by 5 min of normoxia). EVs were isolated from cell supernatant and were co-cultured with macrophages differentiated from THP-1. PD-L1 and hypoxia-inducible factor-1 α (HIF-1α) expressions were measured by flow cytometry, immunofluorescence, and Western blot analysis. Results PD-L1+monocytes were elevated in NSCLC patients with OSA and increased with the severity of OSA and nocturnal desaturation. PD-L1+ macrophages were induced by EVs from NSCLC patients with OSA and positively correlated with HIF-1α expressions. EVs from IH-treated A549 can promote PD-L1 and HIF-1α expression in macrophages and the upregulation of PD-L1 expression was reversed by specific HIF-1α inhibitor. Conclusion IH can enhance the function of EVs derived from lung cancer cells to aggravate immunosuppressive status in macrophages. HIF-1α may play an important role in this process.

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