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Adaptation to Chronic Hypoxia: The Last Word Has Not yet Been Said

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2017) | Viewed by 55067

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Prof. Dr. Michele Samaja

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Department of Health Science, University of Milan, via di Rudinì 8, I-20142 Milan, Italy
Interests: hypoxia; hyperoxia; cardioprotection; brain protection; reoxygenation, molecular mechanisms; apoptosis; autophagy; erythropoietin; nitric oxide; animal models; exercise; high altitude; hemoglobin; oxygen carriers; blood oxygen transport
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Dr. Giuseppina Milano

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Centre Hospitalier Universitaire Vaudois Lausanne, Lausanne, Switzerland
Interests: chronic hypoxia; acute myocardial infarction; cardioprotection; hypoxic pulmonary hypertension; ischemia reperfusion injury; cardiac regeneration; cardiotoxicity; echocardiography; animal models
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Dear Colleagues,

Chronic hypoxia is a common feature in several environmental and pathologic situations. While humans may adapt to moderate and short exposure to hypoxia, this ability is progressively lost with increased severity and duration of oxygen shortage, thereby leading to potentially lethal outcomes. A molecular mechanism, the HIF-1a pathway, was identified as the main orchestrator of the gene, cell, tissue, organ, and body responses to hypoxia. Nevertheless, our knowledge of the complex phenomena derived from chronic hypoxia is still limited and the following areas of research remain still undeveloped:

Identify the major factors that in different tissues shift the threshold at which the mechanisms underlying adaptation to hypoxia switch into maladaptive patterns.
Characterize the responses to chronic hypoxia, with particular concern to redox imbalance and cell death and differentiation, as opposed to those resulting from phenomena that potentially disturb the effects of hypoxia, as wanted or accidental reoxygenation episodes.
Compare the responses to hypoxia with those to hypoxia antagonists, for example hyperoxia and substances that contrast the downstream effects of hypoxia.
Assess whether the classical HIF-1a pathway is sufficient to explain the complexity of the cellular responses to hypoxia, and other oxygen-sensing mechanisms are to be primarily involved.
Dissect the discriminant(s) between the pro-proliferative (e.g., in certain tumors) and the anti-proliferative (e.g., in certain cardiovascular diseases) effects of hypoxia.

Dr. Michele Samaja
Dr. Giuseppina Milano
Guest Editors

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Keywords

chronic hypoxia
intermittent hypoxia
hyperoxia
hypoxia mimetics
hypoxia antagonists
oxygen sensing
hypoxia-inducible factors
adaptation
high altitude
tumor microenvironment
pulmonary dysfunction
cardiovascular disease
apoptosis

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Published Papers (7 papers)

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Research

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15 pages, 2456 KiB

Open AccessArticle

Mechanisms of Cardiovascular Protection Associated with Intermittent Hypobaric Hypoxia Exposure in a Rat Model: Role of Oxidative Stress

by Miguel Aguilar, Alejandro González-Candia, Jorge Rodríguez, Catalina Carrasco-Pozo, Daniel Cañas, Claudio García-Herrera, Emilio A. Herrera and Rodrigo L. Castillo

Int. J. Mol. Sci. 2018, 19(2), 366; https://doi.org/10.3390/ijms19020366 - 26 Jan 2018

Cited by 32 | Viewed by 7479

Abstract

More than 140 million people live and works (in a chronic or intermittent form) above 2500 m worldwide and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 55,000 persons work in high altitude shifts, where stays at lowlands and interspersed with working stays at highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders, due to an increase in free radical formation and a decrease in antioxidant capacity. However, in animal models, intermittent hypoxia (IH) induce preconditioning, like responses and cardioprotection. Here, we aimed to describe in a rat model the responses on cardiac and vascular function to 4 cycles of intermittent hypobaric hypoxia (IHH). Twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH, and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days hypoxia + 4 days normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the first and fourth cycle, cardiac structural, and functional variables were determined by echocardiography. Thereafter, ex vivo vascular function and biomechanical properties were determined in femoral arteries by wire myography. We further measured cardiac oxidative stress biomarkers (4-Hydroxy-nonenal, HNE; nytrotirosine, NT), reactive oxygen species (ROS) sources (NADPH and mitochondrial), and antioxidant enzymes activity (catalase, CAT; glutathione peroxidase, GPx, and superoxide dismutase, SOD). Our results show a higher ejection and shortening fraction of the left ventricle function by the end of the 4th cycle. Further, femoral vessels showed an improvement of vasodilator capacity and diminished stiffening. Cardiac tissue presented a higher expression of antioxidant enzymes and mitochondrial ROS formation in IHH, as compared with normobaric hypoxic controls. IHH exposure determines a preconditioning effect on the heart and femoral artery, both at structural and functional levels, associated with the induction of antioxidant defence mechanisms. However, mitochondrial ROS generation was increased in cardiac tissue. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection. Full article

(This article belongs to the Special Issue Adaptation to Chronic Hypoxia: The Last Word Has Not yet Been Said)

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15 pages, 5165 KiB

Open AccessArticle

IGF-1 Attenuates Hypoxia-Induced Atrophy but Inhibits Myoglobin Expression in C2C12 Skeletal Muscle Myotubes

by Eva L. Peters, Sandra M. Van der Linde, Ilse S. P. Vogel, Mohammad Haroon, Carla Offringa, Gerard M. J. De Wit, Pieter Koolwijk, Willem J. Van der Laarse and Richard T. Jaspers

Int. J. Mol. Sci. 2017, 18(9), 1889; https://doi.org/10.3390/ijms18091889 - 1 Sep 2017

Cited by 16 | Viewed by 8073

Abstract

Chronic hypoxia is associated with muscle wasting and decreased oxidative capacity. By contrast, training under hypoxia may enhance hypertrophy and increase oxidative capacity as well as oxygen transport to the mitochondria, by increasing myoglobin (Mb) expression. The latter may be a feasible strategy to prevent atrophy under hypoxia and enhance an eventual hypertrophic response to anabolic stimulation. Mb expression may be further enhanced by lipid supplementation. We investigated individual and combined effects of hypoxia, insulin-like growth factor (IGF)-1 and lipids, in mouse skeletal muscle C2C12 myotubes. Differentiated C2C12 myotubes were cultured for 24 h under 20%, 5% and 2% oxygen with or without IGF-1 and/or lipid treatment. In culture under 20% oxygen, IGF-1 induced 51% hypertrophy. Hypertrophy was only 32% under 5% and abrogated under 2% oxygen. This was not explained by changes in expression of genes involved in contractile protein synthesis or degradation, suggesting a reduced rate of translation rather than of transcription. Myoglobin mRNA expression increased by 75% under 5% O₂ but decreased by 50% upon IGF-1 treatment under 20% O₂, compared to control. Inhibition of mammalian target of rapamycin (mTOR) activation using rapamycin restored Mb mRNA expression to control levels. Lipid supplementation had no effect on Mb gene expression. Thus, IGF-1-induced anabolic signaling can be a strategy to improve muscle size under mild hypoxia, but lowers Mb gene expression. Full article

(This article belongs to the Special Issue Adaptation to Chronic Hypoxia: The Last Word Has Not yet Been Said)

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19 pages, 2657 KiB

Open AccessArticle

Thirty Minutes of Hypobaric Hypoxia Provokes Alterations of Immune Response, Haemostasis, and Metabolism Proteins in Human Serum

by Jochen Hinkelbein, Stefanie Jansen, Ivan Iovino, Sylvia Kruse, Moritz Meyer, Fabrizio Cirillo, Hendrik Drinhaus, Andreas Hohn, Corinna Klein, Edoardo De Robertis and Dirk Beutner

Int. J. Mol. Sci. 2017, 18(9), 1882; https://doi.org/10.3390/ijms18091882 - 31 Aug 2017

Cited by 17 | Viewed by 6688

Abstract

Hypobaric hypoxia (HH) during airline travel induces several (patho-) physiological reactions in the human body. Whereas severe hypoxia is investigated thoroughly, very little is known about effects of moderate or short-term hypoxia, e.g. during airline flights. The aim of the present study was to analyse changes in serum protein expression and activation of signalling cascades in human volunteers staying for 30 min in a simulated altitude equivalent to airline travel. After approval of the local ethics committee, 10 participants were exposed to moderate hypoxia (simulation of 2400 m or 8000 ft for 30 min) in a hypobaric pressure chamber. Before and after hypobaric hypoxia, serum was drawn, centrifuged, and analysed by two-dimensional gel electrophoresis (2-DIGE) and matrix-assisted laser desorption/ionization followed by time-of-flight mass spectrometry (MALDI-TOF). Biological functions of regulated proteins were identified using functional network analysis (GeneMania^®, STRING^®, and Perseus^® software). In participants, oxygen saturation decreased from 98.1 ± 1.3% to 89.2 ± 1.8% during HH. Expression of 14 spots (i.e., 10 proteins: ALB, PGK1, APOE, GAPDH, C1QA, C1QB, CAT, CA1, F2, and CLU) was significantly altered. Bioinformatic analysis revealed an association of the altered proteins with the signalling cascades “regulation of haemostasis” (four proteins), “metabolism” (five proteins), and “leukocyte mediated immune response” (five proteins). Even though hypobaric hypoxia was short and moderate (comparable to an airliner flight), analysis of protein expression in human subjects revealed an association to immune response, protein metabolism, and haemostasis Full article

(This article belongs to the Special Issue Adaptation to Chronic Hypoxia: The Last Word Has Not yet Been Said)

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18 pages, 3173 KiB

Open AccessArticle

Mechanism Governing Human Kappa-Opioid Receptor Expression under Desferrioxamine-Induced Hypoxic Mimic Condition in Neuronal NMB Cells

by Jennifer Babcock, Alberto Herrera, George Coricor, Christopher Karch, Alexander H. Liu, Aida Rivera-Gines and Jane L. Ko

Int. J. Mol. Sci. 2017, 18(1), 211; https://doi.org/10.3390/ijms18010211 - 20 Jan 2017

Cited by 5 | Viewed by 5486

Abstract

Cellular adaptation to hypoxia is a protective mechanism for neurons and relevant to cancer. Treatment with desferrioxamine (DFO) to induce hypoxia reduced the viability of human neuronal NMB cells. Surviving/attached cells exhibited profound increases of expression of the human kappa-opioid receptor (hKOR) and hypoxia inducible factor-1α (HIF-1α). The functional relationship between hKOR and HIF-1α was investigated using RT-PCR, Western blot, luciferase reporter, mutagenesis, siRNA and receptor-ligand binding assays. In surviving neurons, DFO increased HIF-1α expression and its amount in the nucleus. DFO also dramatically increased hKOR expression. Two (designated as HIFC and D) out of four potential HIF response elements of the hKOR gene (HIFA–D) synergistically mediated the DFO response. Mutation of both elements completely abolished the DFO-induced effect. The CD11 plasmid (containing HIFC and D with an 11 bp spacing) produced greater augmentation than that of the CD17 plasmid (HIFC and D with a 17 bp-spacing), suggesting that a proper topological interaction of these elements synergistically enhanced the promoter activity. HIF-1α siRNA knocked down the increase of endogenous HIF-1α messages and diminished the DFO-induced increase of hKOR expression. Increased hKOR expression resulted in the up-regulation of hKOR protein. In conclusion, the adaptation of neuronal hKOR under hypoxia was governed by HIF-1, revealing a new mechanism of hKOR regulation. Full article

(This article belongs to the Special Issue Adaptation to Chronic Hypoxia: The Last Word Has Not yet Been Said)

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Review

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19 pages, 2912 KiB

Open AccessReview

Adverse Intrauterine Environment and Cardiac miRNA Expression

by Mitchell C. Lock, Kimberley J. Botting, Ross L. Tellam, Doug Brooks and Janna L. Morrison

Int. J. Mol. Sci. 2017, 18(12), 2628; https://doi.org/10.3390/ijms18122628 - 6 Dec 2017

Cited by 24 | Viewed by 9167

Abstract

Placental insufficiency, high altitude pregnancies, maternal obesity/diabetes, maternal undernutrition and stress can result in a poor setting for growth of the developing fetus. These adverse intrauterine environments result in physiological changes to the developing heart that impact how the heart will function in postnatal life. The intrauterine environment plays a key role in the complex interplay between genes and the epigenetic mechanisms that regulate their expression. In this review we describe how an adverse intrauterine environment can influence the expression of miRNAs (a sub-set of non-coding RNAs) and how these changes may impact heart development. Potential consequences of altered miRNA expression in the fetal heart include; Hypoxia inducible factor (HIF) activation, dysregulation of angiogenesis, mitochondrial abnormalities and altered glucose and fatty acid transport/metabolism. It is important to understand how miRNAs are altered in these adverse environments to identify key pathways that can be targeted using miRNA mimics or inhibitors to condition an improved developmental response. Full article

(This article belongs to the Special Issue Adaptation to Chronic Hypoxia: The Last Word Has Not yet Been Said)

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24 pages, 686 KiB

Open AccessReview

Comparative Response of Brain to Chronic Hypoxia and Hyperoxia

by Laura Terraneo and Michele Samaja

Int. J. Mol. Sci. 2017, 18(9), 1914; https://doi.org/10.3390/ijms18091914 - 7 Sep 2017

Cited by 65 | Viewed by 7994

Abstract

Two antithetic terms, hypoxia and hyperoxia, i.e., insufficient and excess oxygen availability with respect to needs, are thought to trigger opposite responses in cells and tissues. This review aims at summarizing the molecular and cellular mechanisms underlying hypoxia and hyperoxia in brain and cerebral tissue, a context that may prove to be useful for characterizing not only several clinically relevant aspects, but also aspects related to the evolution of oxygen transport and use by the tissues. While the response to acute hypoxia/hyperoxia presumably recruits only a minor portion of the potentially involved cell machinery, focusing into chronic conditions, instead, enables to take into consideration a wider range of potential responses to oxygen-linked stress, spanning from metabolic to genic. We will examine how various brain subsystems, including energetic metabolism, oxygen sensing, recruitment of pro-survival pathways as protein kinase B (Akt), mitogen-activated protein kinases (MAPK), neurotrophins (BDNF), erythropoietin (Epo) and its receptors (EpoR), neuroglobin (Ngb), nitric oxide (NO), carbon monoxide (CO), deal with chronic hypoxia and hyperoxia to end-up with the final outcomes, oxidative stress and brain damage. A more complex than expected pattern results, which emphasizes the delicate balance between the severity of the stress imposed by hypoxia and hyperoxia and the recruitment of molecular and cellular defense patterns. While for certain functions the expectation that hypoxia and hyperoxia should cause opposite responses is actually met, for others it is not, and both emerge as dangerous treatments. Full article

(This article belongs to the Special Issue Adaptation to Chronic Hypoxia: The Last Word Has Not yet Been Said)

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13 pages, 877 KiB

Open AccessReview

Targeting Tumor Adaption to Chronic Hypoxia: Implications for Drug Resistance, and How It Can Be Overcome

by Jae-Young Kim and Joo-Yong Lee

Int. J. Mol. Sci. 2017, 18(9), 1854; https://doi.org/10.3390/ijms18091854 - 25 Aug 2017

Cited by 64 | Viewed by 8739

Abstract

The rapid and uncontrolled proliferation of tumors limits the availability of oxygen and nutrients supplied from the tumor vasculature, thus exposing them to low oxygen environments. Thus, diminished oxygen availability, or hypoxia, is the most common microenvironment feature of nearly all solid tumors. All living cells have the ability to sense changes in oxygen tension and adapt to this stress to preserve survival. Likewise, cancer cells adapt to chronic hypoxic stress via several mechanisms, including promotion of angiogenic factor production, metabolic shift to consume less oxygen, and reduction of apoptotic potential. Adaptation of tumor cells to hypoxia is believed to be the main driver for selection of more invasive and therapy-resistant cancer phenotypes. In this review, we discuss molecular mechanisms by which tumor cells adapt to hypoxia, with a specific focus on hypoxia-inducible factor (HIF) transcription factor. We further discuss the current understandings on hypoxia-mediated drug resistance and strategies to overcome it. Full article

(This article belongs to the Special Issue Adaptation to Chronic Hypoxia: The Last Word Has Not yet Been Said)

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