scholarly journals Obstructive Sleep Apnea Activates HIF-1 in a Hypoxia Dose-Dependent Manner in HCT116 Colorectal Carcinoma Cells

2019 ◽  
Vol 20 (2) ◽  
pp. 445 ◽  
Author(s):  
Chloe-Anne Martinez ◽  
Bernadette Kerr ◽  
Charley Jin ◽  
Peter Cistulli ◽  
Kristina Cook
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Cancer Progression ◽  
Intermittent Hypoxia ◽  
Target Genes ◽  
Chronic Hypoxia ◽  
Significant Proportion ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) affects a significant proportion of the population and is linked to increased rates of cancer development and a worse cancer outcome. OSA is characterized by nocturnal intermittent hypoxia and animal models of OSA-like intermittent hypoxia show increased tumor growth and metastasis. Advanced tumors typically have regions of chronic hypoxia, activating the transcription factor, HIF-1, which controls the expression of genes involved in cancer progression. Rapid intermittent hypoxia from OSA has been proposed to increase HIF-1 activity and this may occur in tumors. The effect of exposing a developing tumor to OSA-like intermittent hypoxia is largely unknown. We have built a cell-based model of physiological OSA tissue oxygenation in order to study the effects of intermittent hypoxia in HCT116 colorectal cancer cells. We found that HIF-1α increases following intermittent hypoxia and that the expression of HIF-target genes increases, including those involved in glycolysis, the hypoxic pathway and extracellular matrix remodeling. Expression of these genes acts as a ‘hypoxic’ signature which is associated with a worse prognosis. The total dose of hypoxia determined the magnitude of change in the hypoxic signature rather than the frequency or duration of hypoxia-reoxygenation cycles per se. Finally, transcription of HIF1A mRNA differs in response to chronic and intermittent hypoxia suggesting that HIF-1α may be regulated at the transcriptional level in intermittent hypoxia and not just by the post-translational oxygen-dependent degradation pathway seen in chronic hypoxia.

scholarly journals miR-21-5p Under-Expression in Patients with Obstructive Sleep Apnea Modulates Intermittent Hypoxia with Re-Oxygenation-Induced-Cell Apoptosis and Cytotoxicity by Targeting Pro-Inflammatory TNF-α-TLR4 Signaling

2020 ◽  
Vol 21 (3) ◽  
pp. 999
Author(s):  
Yung-Che Chen ◽  
Po-Yuan Hsu ◽  
Mao-Chang Su ◽  
Chien-Hung Chin ◽  
Chia-Wei Liou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Cell Apoptosis ◽  
Intermittent Hypoxia ◽  
Target Genes ◽  
Apnea Hypopnea Index ◽  
Gene Expressions ◽  
Obstructive Sleep ◽  
Tnf Α

The purpose of this study is to explore the anti-inflammatory role of microRNAs (miR)-21 and miR-23 targeting the TLR/TNF-α pathway in response to chronic intermittent hypoxia with re-oxygenation (IHR) injury in patients with obstructive sleep apnea (OSA). Gene expression levels of the miR-21/23a, and their predicted target genes were assessed in peripheral blood mononuclear cells from 40 treatment-naive severe OSA patients, and 20 matched subjects with primary snoring (PS). Human monocytic THP-1 cell lines were induced to undergo apoptosis under IHR exposures, and transfected with miR-21-5p mimic. Both miR-21-5p and miR-23-3p gene expressions were decreased in OSA patients as compared with that in PS subjects, while TNF-α gene expression was increased. Both miR-21-5p and miR-23-3p gene expressions were negatively correlated with apnea hypopnea index and oxygen desaturation index, while TNF-α gene expression positively correlated with apnea hypopnea index. In vitro IHR treatment resulted in decreased miR-21-5p and miR-23-3p expressions. Apoptosis, cytotoxicity, and gene expressions of their predicted target genes—including TNF-α, ELF2, NFAT5, HIF-2α, IL6, IL6R, EDNRB, and TLR4—were all increased in response to IHR, while all were reversed with miR-21-5p mimic transfection under IHR condition. The findings provide biological insight into mechanisms by which IHR-suppressed miRs protect cell apoptosis via inhibit inflammation, and indicate that over-expression of the miR-21-5p may be a new therapy for OSA.

scholarly journals Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers

2009 ◽  
Vol 106 (5) ◽  
pp. 1538-1544 ◽  
Author(s):  
Mariam Louis ◽  
Naresh M. Punjabi
Keyword(s):  
Obstructive Sleep Apnea ◽  
Insulin Secretion ◽  
Sleep Apnea ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Healthy Volunteers ◽  
Intermittent Hypoxia ◽  
Metabolic Dysfunction ◽  
Glucose Effectiveness ◽  
Obstructive Sleep

Accumulating evidence suggests that obstructive sleep apnea is associated with alterations in glucose metabolism. Although the pathophysiology of metabolic dysfunction in obstructive sleep apnea is not well understood, studies of murine models indicate that intermittent hypoxemia has an important contribution. However, corroborating data on the metabolic effects of intermittent hypoxia on glucose metabolism in humans are not available. Thus the primary aim of this study was to characterize the acute effects of intermittent hypoxia on glucose metabolism. Thirteen healthy volunteers were subjected to 5 h of intermittent hypoxia or normoxia during wakefulness in a randomized order on two separate days. The intravenous glucose tolerance test (IVGTT) was used to assess insulin-dependent and insulin-independent measures of glucose disposal. The IVGTT data were analyzed using the minimal model to determine insulin sensitivity (SI) and glucose effectiveness (SG). Drops in oxyhemoglobin saturation were induced during wakefulness at an average rate of 24.3 events/h. Compared with the normoxia condition, intermittent hypoxia was associated with a decrease in SI [4.1 vs. 3.4 (mU/l)−1·min−1; P = 0.0179] and SG (1.9 vs. 1.3 min−1×10−2, P = 0.0065). Despite worsening insulin sensitivity with intermittent hypoxia, pancreatic insulin secretion was comparable between the two conditions. Heart rate variability analysis showed the intermittent hypoxia was associated with a shift in sympathovagal balance toward an increase in sympathetic nervous system activity. The average R-R interval on the electrocardiogram was 919.0 ms during the normoxia condition and 874.4 ms during the intermittent hypoxia condition ( P < 0.04). Serum cortisol levels after intermittent hypoxia and normoxia were similar. Hypoxic stress in obstructive sleep apnea may increase the predisposition for metabolic dysfunction by impairing insulin sensitivity, glucose effectiveness, and insulin secretion.

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