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Pathophysiological and Molecular Signaling Impacts of Chronic Hypoxia and Intermittent Hypoxia

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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 9654

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Special Issue Editors

Prof. Dr. Gilles Faury

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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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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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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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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

Published Papers (5 papers)

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Research

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13 pages, 1342 KiB

Open AccessArticle

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

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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 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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15 pages, 2786 KiB

Open AccessArticle

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 3 | Viewed by 2006

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 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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Review

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17 pages, 814 KiB

Open AccessReview

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

Viewed by 1297

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 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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22 pages, 1603 KiB

Open AccessReview

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 1 | Viewed by 1151

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 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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18 pages, 1799 KiB

Open AccessReview

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 9 | Viewed by 2478

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 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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