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Pathophysiological and Molecular Signaling Impacts of Chronic Hypoxia and Intermittent Hypoxia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 12515

Special Issue Editors

Prof. Dr. Gilles Faury

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Guest Editor
Université Grenoble Alpes, INSERM U1300, CHU Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France
Interests: cardiovascular physiology; elastic fibers in vascular development, genetic diseases and aging; intermittent hypoxia-induced cardiovascular dysfunction; biomechanics; elastin receptors; calcium signalling; pharmacotherapy
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Jean Louis D. Peṕin

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Guest Editor
EFCR Laboratory, Grenoble Alpes University Hospital, 38043 Grenoble, France
Interests: obstructive sleep apnea; obesity hypoventilation syndrome; central sleep apnea; coronary artery bypass graft (CABG); heart bypass surgery
Dr. Samuel Verges

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Guest Editor
HP2 Laboratory, INSERM U1300, Grenoble Alpes University, CHU Grenoble Alpes, 38400 Grenoble, France
Interests: physiology; respiratory system; sport sciences

Special Issue Information

Dear Colleagues, 

Changes—especially limitations—in the oxygenation of an organism have important impacts on organ function and the general physiology. Two major situations impact oxygenation: i) chronic hypoxia (CH), due to pathological situations chronically limiting blood oxygenation such as chronic obstructive pulmonary diseases, including emphysema, or life at high altitudes; and ii) intermittent hypoxia (IH), due to the intermittent obstruction of the upper airways, especially related to sleep apnea (obstructive sleep apnea syndrome). These two conditions both induce hypoxemia, with consequences on most systems, including the cardiovascular, pulmonary and nervous systems, as well as the metabolism and associated organs/tissues (liver, fat, etc.). However, some CH and IH pathophysiological impacts are rather similar (hematocrit elevation, the activation of hypoxia-inducible factor (HIF) pathways, etc.), while other impacts are divergent (pulmonary hypertension in CH, systemic hypertension in IH, distinct patterns of HIF activation in IH and CH, etc.). Additionally, some CH and IH impacts could be seen as beneficial for the organism (e.g., preconditioning limiting the severity of further cardiovascular events), while other effects are clearly deleterious (e.g., higher risk of cardiac infarct in IH). Thus, this Special Issue intends to collect the latest results on the physiopathological consequences of chronic hypoxia or intermittent hypoxia, allowing for a better understanding, as well as a dissection of the downstream cellular and molecular mechanisms involved in the structural and functional changes observed in concerned persons, patients or animal models. We hope this compilation of works permits a reflection and better understanding of the similarities and differences of the mechanisms and impacts of CH and IH. Experimental papers and review articles in basic science, clinical or translational fields are welcome.

Prof. Dr. Gilles Faury
Prof. Dr. Jean Louis D. Peṕin
Dr. Samuel Verges
Guest Editors

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Keywords

  • intermittent hypoxia
  • chronic hypoxia
  • sleep apnea
  • altitude
  • hypoxia-induced factor
  • signaling pathways
  • cardiovascular system
  • metabolism
  • pulmonary system
  • nervous system
  • disease
  • preconditioning
  • patients
  • animal models
  • cellular models

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Published Papers (5 papers)

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13 pages, 1342 KiB  
Article
Differential Impact of Intermittent vs. Sustained Hypoxia on HIF-1, VEGF and Proliferation of HepG2 Cells
by Mélanie Minoves, Florence Hazane-Puch, Giorgia Moriondo, Antoine Boutin-Paradis, Emeline Lemarié, Jean-Louis Pépin, Diane Godin-Ribuot and Anne Briançon-Marjollet
Int. J. Mol. Sci. 2023, 24(8), 6875; https://doi.org/10.3390/ijms24086875 - 7 Apr 2023
Cited by 4 | Viewed by 2546
Abstract
Obstructive sleep apnea (OSA) is an emerging risk factor for cancer occurrence and progression, mainly mediated by intermittent hypoxia (IH). Systemic IH, a main landmark of OSA, and local sustained hypoxia (SH), a classical feature at the core of tumors, may act separately [...] Read more.
Obstructive sleep apnea (OSA) is an emerging risk factor for cancer occurrence and progression, mainly mediated by intermittent hypoxia (IH). Systemic IH, a main landmark of OSA, and local sustained hypoxia (SH), a classical feature at the core of tumors, may act separately or synergistically on tumor cells. Our aim was to compare the respective consequences of intermittent and sustained hypoxia on HIF-1, endothelin-1 and VEGF expression and on cell proliferation and migration in HepG2 liver tumor cells. Wound healing, spheroid expansion, proliferation and migration were evaluated in HepG2 cells following IH or SH exposure. The HIF-1α, endothelin-1 and VEGF protein levels and/or mRNA expression were assessed, as were the effects of HIF-1 (acriflavine), endothelin-1 (macitentan) and VEGF (pazopanib) inhibition. Both SH and IH stimulated wound healing, spheroid expansion and proliferation of HepG2 cells. HIF-1 and VEGF, but not endothelin-1, expression increased with IH exposure but not with SH exposure. Acriflavine prevented the effects of both IH and SH, and pazopanib blocked those of IH but not those of SH. Macitentan had no impact. Thus, IH and SH stimulate hepatic cancer cell proliferation via distinct signaling pathways that may act synergistically in OSA patients with cancer, leading to enhanced tumor progression. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Signaling Impacts of Chronic Hypoxia and Intermittent Hypoxia)
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Figure 1

Figure 1
<p>In vitro sustained hypoxia and intermittent hypoxia increase hepatic tumor cell expansion. (<b>a</b>) Representative illustrations of HepG2 cell invasiveness in 2D, assessed by wound healing, before and after 7 days of normoxia, intermittent hypoxia or sustained hypoxia exposure (white scale bar = 600 µm). (<b>b</b>) Wound healing, expressed as a % of repaired area compared with normoxia, of HepG2 cells exposed to 7 days of normoxia, intermittent hypoxia or sustained hypoxia; <span class="html-italic">n</span> = 5 experiments per group with at least 3 wells/experiment. Intermittent hypoxia global effect <span class="html-italic">p</span> &lt; 0.00001, ** <span class="html-italic">p</span> &lt; 0.01 on D4 and D7 for IH vs. N and on D5 and D7 for SH vs. N and *** <span class="html-italic">p</span> &lt; 0.001 for IH vs. N on D5, one-way repeated measures ANOVA. Sustained hypoxia global effect <span class="html-italic">p</span> = 0.006, one-way repeated measures ANOVA and ** <span class="html-italic">p</span> &lt; 0.01 on D5 and on day 7. (<b>c</b>) Representative illustrations of HepG2 spheroid expansion before and after 5, 7, 14 and 21 days of normoxia, intermittent hypoxia or sustained hypoxia exposure (white scale bar = 1000 µm). (<b>d</b>) HepG2 spheroid expansion in response to 21 days of intermittent hypoxia; <span class="html-italic">n</span> = 5 experiments per group (6 to 12 wells/experiment). * <span class="html-italic">p</span> &lt; 0.05, repeated measures ANOVA). Post hoc analysis showed significant differences * <span class="html-italic">p</span> &lt; 0.05 on days 7 and 21 of exposure. HepG2 spheroid expansion in response to 21 days of sustained hypoxia; <span class="html-italic">n</span> = 5 experiments per group (6 to 12 wells/experiment). * <span class="html-italic">p</span> &lt; 0.01, repeated measures ANOVA. Post hoc analysis showed significant differences * <span class="html-italic">p</span> &lt; 0.05 on days 7, 14 and 21 of exposure.</p> Full article ">Figure 2
<p>Sustained hypoxia and intermittent hypoxia increase cell proliferation in vitro. (<b>a</b>) Proliferation, expressed as a % of normoxia values, of viable HepG2 cells quantified by MTT staining after 5 days of normoxia, intermittent hypoxia or sustained hypoxia exposure; <span class="html-italic">n</span> = 3 independent experiments/group (at least 18 wells/group). * <span class="html-italic">p</span> &lt; 0.05 and ** <span class="html-italic">p</span> &lt; 0.01 on D5 for IH cells compared with normoxia cells, and <span class="html-italic">p</span> &lt; 0.05 for SH cells compared with N cells, Mann–Whitney U test. (<b>b</b>) Migration, expressed as a % of normoxia values, of HepG2 cells after 2 days of normoxia, intermittent hypoxia or sustained hypoxia exposure; <span class="html-italic">n</span> = 3 independent experiment/group (6 wells/group: 2 transwells/experiments). Mann–Whitney U test.</p> Full article ">Figure 3
<p>In vitro effects of IH and SH on HIF-1α gene expression, and VEGF gene and protein expression. (<b>a</b>) Intermittent hypoxia is associated with an increase in HIF-1α and VEGF gene expressions in HepG2 cells after 5 days of exposure. The levels of HIF-1α and VEGF gene expression were measured by RT-QPCR; <span class="html-italic">n</span> = 3 independent experiments/group. * <span class="html-italic">p</span> &lt; 0.05, Mann–Whitney U test. (<b>b</b>) VEGF expression increases in HepG2 cells after 5 days of IH but not SH exposure. The levels of VEGF protein in the cell’s supernatant were measured by ELISA; <span class="html-italic">n</span> = 3 independent experiments/group. * <span class="html-italic">p</span> &lt; 0.05) Mann–Whitney U test.</p> Full article ">Figure 4
<p>Effects of acriflavine and pazopanib on wound healing and proliferation under sustained hypoxia or intermittent hypoxia. (<b>a</b>) Wound healing, expressed as % of repaired area, of HepG2 cells exposed to 5 days of normoxia (N), intermittent hypoxia (IH) or sustained hypoxia (SH) and treated or not by acriflavine (Acri); <span class="html-italic">n</span> = 3 experiments per group with at least 3 wells/experiment. ** <span class="html-italic">p</span> &lt; 0.01 on D5 for IH acriflavine-treated cells compared with IH untreated and * <span class="html-italic">p</span> &lt; 0.05 on D5 for SH acriflavine-treated cells compared with SH untreated cells, Mann–Whitney U test. (<b>b</b>) Wound healing, expressed as a % of repaired area, of HepG2 cells exposed to 5 days of normoxia, intermittent hypoxia or sustained hypoxia and treated or not by pazopanib (Pazo); <span class="html-italic">n</span> = 3 experiments per group with at least 3 wells/experiment. ** <span class="html-italic">p</span> &lt; 0.01 on D5 for IH pazopanib-treated cells compared with IH untreated, Mann–Whitney U test. (<b>c</b>) Proliferation, expressed as a % of Normoxia values, of viable HepG2 cells quantified by MTT staining after 5 days of normoxia, intermittent hypoxia or sustained hypoxia and treated or not by acriflavine (Acri); <span class="html-italic">n</span> = 3 independent experiments/group, 6 to 12 wells/group: at least 2 wells/experiment. * <span class="html-italic">p</span> &lt; 0.05 on D5 for IH acriflavine-treated cells compared with IH untreated, <span class="html-italic">p</span> &lt; 0.05 for CH acriflavine-treated cells compared with CH untreated cells, Mann–Whitney U test. (<b>d</b>) Proliferation, expressed as a % of control values (respectively N, IH or CH), of viable HepG2 cells quantified by MTT staining after 5 days of normoxia, intermittent hypoxia or sustained hypoxia and treated or not by pazopanib (Pazo); <span class="html-italic">n</span> = at least 3 independent experiments/group (9 wells/group: at least 2 wells/experiment). * <span class="html-italic">p</span> &lt; 0.05 on D5 for IH pazopanib-treated cells compared with IH untreated, Mann–Whitney U test.</p> Full article ">
15 pages, 2786 KiB  
Article
Loss of Blood-Brain Barrier Integrity in an In Vitro Model Subjected to Intermittent Hypoxia: Is Reversion Possible with a HIF-1α Pathway Inhibitor?
by Anne Cloé Voirin, Morgane Chatard, Anne Briançon-Marjollet, Jean Louis Pepin, Nathalie Perek and Frederic Roche
Int. J. Mol. Sci. 2023, 24(5), 5062; https://doi.org/10.3390/ijms24055062 - 6 Mar 2023
Cited by 4 | Viewed by 2392
Abstract
Several sleep-related breathing disorders provoke repeated hypoxia stresses, which potentially lead to neurological diseases, such as cognitive impairment. Nevertheless, consequences of repeated intermittent hypoxia on the blood-brain barrier (BBB) are less recognized. This study compared two methods of intermittent hypoxia induction on the [...] Read more.
Several sleep-related breathing disorders provoke repeated hypoxia stresses, which potentially lead to neurological diseases, such as cognitive impairment. Nevertheless, consequences of repeated intermittent hypoxia on the blood-brain barrier (BBB) are less recognized. This study compared two methods of intermittent hypoxia induction on the cerebral endothelium of the BBB: one using hydralazine and the other using a hypoxia chamber. These cycles were performed on an endothelial cell and astrocyte coculture model. Na-Fl permeability, tight junction protein, and ABC transporters (P-gp and MRP-1) content were evaluated with or without HIF-1 inhibitors YC-1. Our results demonstrated that hydralazine as well as intermittent physical hypoxia progressively altered BBB integrity, as shown by an increase in Na-Fl permeability. This alteration was accompanied by a decrease in concentration of tight junction proteins ZO-1 and claudin-5. In turn, microvascular endothelial cells up-regulated the expression of P-gp and MRP-1. An alteration was also found under hydralazine after the third cycle. On the other hand, the third intermittent hypoxia exposure showed a preservation of BBB characteristics. Furthermore, inhibition of HIF-1α with YC-1 prevented BBB dysfunction after hydralazine treatment. In the case of physical intermittent hypoxia, we observed an incomplete reversion suggesting that other biological mechanisms may be involved in BBB dysfunction. In conclusion, intermittent hypoxia led to an alteration of the BBB model with an adaptation observed after the third cycle. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Signaling Impacts of Chronic Hypoxia and Intermittent Hypoxia)
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Figure 1

Figure 1
<p>HIF-1α level by b.End3 under different conditions. Treatment with hydralazine for 2 h, hydralazine 2 h + recovery 6 h, pretreatment with YC-1 followed by hydralazine, or physical intermittent hypoxia. Results are presented as mean values ± s.e.m (<span class="html-italic">n</span> = 5). ** <span class="html-italic">p</span> &lt; 0.01 versus normoxic level.</p> Full article ">Figure 2
<p>Apparent permeability measurement evaluated by Na-Fl BBB passage (<b>A</b>) and transendothelial electrical resistance measurement (TEER) (<b>B</b>), after the BBB model was exposed to hydralazine with or without YC-1 treatment, during three cycles of hydralazine/washing. Results are represented as mean value ± s.e.m (<span class="html-italic">n</span> = 6). Na-Fl: sodium-fluorescein; BBB: blood-brain barrier. * <span class="html-italic">p</span> &lt; 0.05 versus normoxia, # <span class="html-italic">p</span> &lt; 0.05 versus without YC-1 treatment.</p> Full article ">Figure 3
<p>Expressions of ZO-1 (<b>A</b>) and claudin-5 (<b>B</b>) measured by whole-cell ELISA after exposure of cells to hydralazine, with or without YC-1, during three cycles of hydralazine/washing. Results are represented as mean value ± s.e.m (n = 6). * <span class="html-italic">p</span> &lt; 0.05 versus normoxia, # <span class="html-italic">p</span> &lt; 0.05 versus without YC-1 treatment.</p> Full article ">Figure 4
<p>Levels of MRP-1 (<b>A</b>) and P-gp (<b>B</b>) measured by whole cell ELISA after exposure of cells to hydralazine, with or without YC-1, during three cycles. Results are represented as mean value ± s.e.m (n = 6). * <span class="html-italic">p</span> &lt; 0.05 versus normoxia, # <span class="html-italic">p</span> &lt; 0.05 versus without YC-1 treatment.</p> Full article ">Figure 5
<p>Apparent permeability to Na-Fl (<b>A</b>), and transendothelial electrical resistance (TEER) (<b>B</b>) after the blood-brain barrier model was exposed to one to three cycles of intermittent hypoxia with or without YC-1 treatment. Results are represented as mean value ± s.e.m (n = 6) Na-Fl: sodium-fluorescein. * <span class="html-italic">p</span> &lt; 0.05 versus normoxia, # <span class="html-italic">p</span> &lt; 0.05 versus without YC-1 treatment.</p> Full article ">Figure 6
<p>Levels of ZO-1 (<b>A</b>) and claudin-5 (<b>B</b>) evaluated by whole cell ELISA after exposure of cells to 1 to 3 periods of intermittent hypoxia, with or without YC-1. Results are represented as mean value ± s.e.m (n = 6). * <span class="html-italic">p</span> &lt; 0.05 versus normoxia, # <span class="html-italic">p</span> &lt; 0.05 versus without YC-1 treatment.</p> Full article ">Figure 7
<p>Levels of P-gp (<b>A</b>) and MRP-1 (<b>B</b>) measured by whole cell ELISA after exposure of cells to one to three periods of intermittent hypoxia, with or without YC-1. Results are represented as mean value ± s.e.m (n = 6). * <span class="html-italic">p</span> &lt; 0.05 versus normoxia, # <span class="html-italic">p</span> &lt; 0.05 versus without YC-1 treatment.</p> Full article ">Figure 8
<p>Experimental setups for intermittent hypoxia (IH). Hydralazine cycle corresponded to 2 h with hydralazine and 6 h without hydralazine, repeated 3 times. Physical IH was created by alternating phases of 5 min at 2% oxygen and 5 min at 16% oxygen for 2 h, followed by 6 h of normoxia at 16% oxygen, with the whole process was repeated three times for a total duration of 24 h.</p> Full article ">

Review

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17 pages, 814 KiB  
Review
Obstructive Sleep Apnea-Associated Intermittent Hypoxia-Induced Immune Responses in Males, Pregnancies, and Offspring
by Ruolin Song, Tracy L. Baker, Jyoti J. Watters and Sathish Kumar
Int. J. Mol. Sci. 2024, 25(3), 1852; https://doi.org/10.3390/ijms25031852 - 3 Feb 2024
Cited by 1 | Viewed by 2009
Abstract
Obstructive sleep apnea (OSA), a respiratory sleep disorder associated with cardiovascular diseases, is more prevalent in men. However, OSA occurrence in pregnant women rises to a level comparable to men during late gestation, creating persistent effects on both maternal and offspring health. The [...] Read more.
Obstructive sleep apnea (OSA), a respiratory sleep disorder associated with cardiovascular diseases, is more prevalent in men. However, OSA occurrence in pregnant women rises to a level comparable to men during late gestation, creating persistent effects on both maternal and offspring health. The exact mechanisms behind OSA-induced cardiovascular diseases remain unclear, but inflammation and oxidative stress play a key role. Animal models using intermittent hypoxia (IH), a hallmark of OSA, reveal several pro-inflammatory signaling pathways at play in males, such as TLR4/MyD88/NF-κB/MAPK, miRNA/NLRP3, and COX signaling, along with shifts in immune cell populations and function. Limited evidence suggests similarities in pregnancies and offspring. In addition, suppressing these inflammatory molecules ameliorates IH-induced inflammation and tissue injury, providing new potential targets to treat OSA-associated cardiovascular diseases. This review will focus on the inflammatory mechanisms linking IH to cardiovascular dysfunction in males, pregnancies, and their offspring. The goal is to inspire further investigations into the understudied populations of pregnant females and their offspring, which ultimately uncover underlying mechanisms and therapeutic interventions for OSA-associated diseases. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Signaling Impacts of Chronic Hypoxia and Intermittent Hypoxia)
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Figure 1

Figure 1
<p>Comprehensive inflammatory consequences of intermittent hypoxia (IH) exposures. IH-induced oxidative stress causes MAPK and NF-κB activation, leading to an upregulation of NLRP3 inflammasome, pro-inflammatory miRNA, and COX signaling. The releases of inflammatory cytokines, fibrosis- and apoptosis-related factors are increased, accompanied by an elevation in adhesion molecule expression. The figure specifically depicts major inflammatory signaling pathways observed in chronic IH-exposed male subjects. Similar alterations found in gestational IH-exposed pregnant females and their offspring are denoted by * and #, respectively.</p> Full article ">
22 pages, 1603 KiB  
Review
Tau Protein Alterations Induced by Hypobaric Hypoxia Exposure
by Eduardo Pena, Rocio San Martin-Salamanca, Samia El Alam, Karen Flores and Karem Arriaza
Int. J. Mol. Sci. 2024, 25(2), 889; https://doi.org/10.3390/ijms25020889 - 10 Jan 2024
Cited by 2 | Viewed by 1943
Abstract
Tauopathies are a group of neurodegenerative diseases whose central feature is dysfunction of the microtubule-associated protein tau (MAPT). Although the exact etiology of tauopathies is still unknown, it has been hypothesized that their onset may occur up to twenty years before the clear [...] Read more.
Tauopathies are a group of neurodegenerative diseases whose central feature is dysfunction of the microtubule-associated protein tau (MAPT). Although the exact etiology of tauopathies is still unknown, it has been hypothesized that their onset may occur up to twenty years before the clear emergence of symptoms, which has led to questions about whether the prognosis of these diseases can be improved by, for instance, targeting the factors that influence tauopathy development. One such factor is hypoxia, which is strongly linked to Alzheimer’s disease because of its association with obstructive sleep apnea and has been reported to affect molecular pathways related to the dysfunction and aggregation of tau proteins and other biomarkers of neurological damage. In particular, hypobaric hypoxia exposure increases the activation of several kinases related to the hyperphosphorylation of tau in neuronal cells, such as ERK, GSK3β, and CDK5. In addition, hypoxia also increases the levels of inflammatory molecules (IL-β1, IL-6, and TNF-α), which are also associated with neurodegeneration. This review discusses the many remaining questions regarding the influence of hypoxia on tauopathies and the contribution of high-altitude exposure to the development of these diseases. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Signaling Impacts of Chronic Hypoxia and Intermittent Hypoxia)
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Figure 1

Figure 1
<p>Illustration of the mechanism by which kinases cause hyperphosphorylation of tau and the subsequent formation of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) in neuronal cells of the central nervous system during the development of tauopathies. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">Figure 2
<p>Image of the distribution of neurofibrillary tangles (NFTs) during different stages of Alzheimer’s disease (AD). In AD, tau pathology begins in the hippocampus and spreads from the limbic system to the neocortex. A patient’s symptoms depend on the areas of the brain to which tau aggregates (NFTs; shown in orange) spread [<a href="#B61-ijms-25-00889" class="html-bibr">61</a>].</p> Full article ">Figure 3
<p>Influence of hypoxia on tauopathies. Hypoxia activates numerous molecular mechanisms in the body that trigger, for example, increased inflammation, increased DNA damage, kinase and phosphatase dysregulation, and tau pathology, thus contributing to the cognitive deterioration observed in tauopathies (tau: tau protein; pTau: hyperphosphorylated tau protein; ERK: extracellular signal-regulated kinase, GSK3β: glycogen synthase kinase 3 β; CDK5: cyclin-dependent kinase 5; PP2A: protein phosphatase 2 A; NFTs: neurofibrillary tangles; Aβ: β-amyloid protein; IL-β1: interleukin-β1; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α). Created with Canva (Sydney, Australia).</p> Full article ">
18 pages, 1799 KiB  
Review
Neurotrophins in the Neuropathophysiology, Course, and Complications of Obstructive Sleep Apnea—A Narrative Review
by Agata Gabryelska, Szymon Turkiewicz, Marta Ditmer and Marcin Sochal
Int. J. Mol. Sci. 2023, 24(3), 1808; https://doi.org/10.3390/ijms24031808 - 17 Jan 2023
Cited by 11 | Viewed by 2889
Abstract
Obstructive sleep apnea (OSA) is a disorder characterized by chronic intermittent hypoxia and sleep fragmentation due to recurring airway collapse during sleep. It is highly prevalent in modern societies, and due to its pleiotropic influence on the organism and numerous sequelae, it burdens [...] Read more.
Obstructive sleep apnea (OSA) is a disorder characterized by chronic intermittent hypoxia and sleep fragmentation due to recurring airway collapse during sleep. It is highly prevalent in modern societies, and due to its pleiotropic influence on the organism and numerous sequelae, it burdens patients and physicians. Neurotrophins (NTs), proteins that modulate the functioning and development of the central nervous system, such as brain-derived neurotrophic factor (BDNF), have been associated with OSA, primarily due to their probable involvement in offsetting the decline in cognitive functions which accompanies OSA. However, NTs influence multiple aspects of biological functioning, such as immunity. Thus, extensive evaluation of their role in OSA might enlighten the mechanism behind some of its elusive features, such as the increased risk of developing an immune-mediated disease or the association of OSA with cardiovascular diseases. In this review, we examine the interactions between NTs and OSA and discuss their contribution to OSA pathophysiology, complications, as well as comorbidities. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Signaling Impacts of Chronic Hypoxia and Intermittent Hypoxia)
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Figure 1

Figure 1
<p>Neurotrophins pathways. (<b>A</b>) proNTs, including proBDNF and proNGF (proNT-3, proNT-4 in a lesser extent), have pro-apoptotic activity. They make a complex with sortilin and p75NTR, initiating the JNK pathway. (<b>B</b>) Trk family are receptor tyrosine kinases family which shows affinity to NTs. They act through many pathways, such as PI3K/AKT, Ras/MAPK, and PLC/PKC. Akt—serine/threonine protein kinase; Bak—BCL-2 homologous antagonist/killer; BDNF—brain-derived neurotrophic factor; DAG—diacyloglycerol; Fas-L—tumor necrosis factor ligand superfamily member 6; IP3—inositol trisphosphate; JNK—c-Jun N-terminal kinase; MAPK—mitogen-activated protein kinase; MEKK—mitogen-activated protein kinase kinase kinase 1; MKK4—mitogen-activated protein kinase kinase 4; MKK7—mitogen-activated protein kinase kinase 7; NGF—nerve growth factor; NT-3—neurotrophin 3; NT-4—neurotrophin 4; p75NTR—p75 neurotrophic receptor; PI3K—PI3 -kinase type 3; PKC—protein kinase C; proNTs—premature neurotrophins; Ras—KRAS proto-oncogen; TFF—trefoil factor 1; TrkA/B/C—tropomyosin receptor kinase A/B/C.</p> Full article ">Figure 2
<p>The review article scheme. BDNF—brain-derived neurotrophic factor; GDNF—glial-cell line-derived neurotrophic factor; NGF—nerve growth factor; NT3—neurotrophin-3; NT4—neurotrophin 4; OSA—obstructive sleep apnea.</p> Full article ">Figure 3
<p>Summary of basic mechanisms through impaired signaling pathway involved in the development of chosen diseases.</p> Full article ">
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