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Adaptation to Hypoxia: Beyond the Chimera

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 41073

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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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As a world-relevant clinical and environmental issue that affects millions of people worldwide, hypoxia is a source of profound distress within the health, social, and economic spheres. Despite being a potentially lethal condition, the human body possesses reserves that sometimes enable the recruitment of defense mechanisms for survival, at least for relatively acute and non-severe hypoxia episodes. However, full adaptation, defined as “modification of an organism or its parts that makes it more fit for existence under the conditions of its environment” (Merriam-Webster Dictionary), to hypoxia might represent a chimera, as already highlighted in a recent Special Issue of this Journal. This Special Issue will focus on the molecular mechanisms underlying the responses to a lack or excess of oxygen, with emphasis on the link between hypoxia and systems biology. Systems biology can be defined as an approach in biomedical research aimed at understanding the larger picture by putting pieces together, in contrast to the reductionist biology approach, that takes pieces apart. Thus, within the context of assembling a complex puzzle and a utilizing systems biology approach, we welcome contributions aiming at understanding the effects of hypoxia on subsystems of the human body.

The horizontal arguments that will form this Special Issue may include, but are not limited to, the following:

Pulmonary hypoxia, with special reference to the right and left ventricular functions;
Myocardial and muscle hypoxia, with special reference to the contractile function and resistance against ischemia-reperfusion injury;
Cerebral hypoxia, with special reference to the viability of the nervous system when challenged by oxygen deficit;
Kidney hypoxia, with special reference to the response of the renal system to anemia;
Mesenteric hypoxia, with special reference to the alterations induced by oxygen deficit;
The effects of hypoxia on the immunological and erythropoietic systems.

These subsystems may be analyzed with respect to various mechanisms, or vertical arguments, that include, but are not limited to, the following:

Handling of NO;
Recruitment of pluripotent cells;
Hypoxia-sensitive genes and proteins;
Metabolic derangements;
Control of the redox imbalance.

We believe that by exploring the horizontal and vertical arguments cited above, we will be able to further understand not only the mechanisms whereby hypoxia represents a burden on the Western world, but also to elucidate the differential response to pathological (e.g., ARDS, COPD, COVID-19) and physiological (e.g., altitude) hypoxic challenges.

Prof. Dr. Michele Samaja
Dr. Giuseppina Milano
Guest Editors

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Keywords

adaptation
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 (9 papers)

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Research

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16 pages, 1601 KiB

Open AccessArticle

Blood Metabolite Profiling of Antarctic Expedition Members: An ¹H NMR Spectroscopy-Based Study

by Laura Del Coco, Marco Greco, Alessandra Inguscio, Anas Munir, Antonio Danieli, Luca Cossa, Debora Musarò, Maria Rosaria Coscia, Francesco Paolo Fanizzi and Michele Maffia

Int. J. Mol. Sci. 2023, 24(9), 8459; https://doi.org/10.3390/ijms24098459 - 8 May 2023

Cited by 2 | Viewed by 2492

Abstract

Serum samples from eight participants during the XV winter-over at Concordia base (Antarctic expedition) collected at defined time points, including predeparture, constituted the key substrates for a specific metabolomics study. To ascertain acute changes and chronic adaptation to hypoxia, the metabolic profiles of the serum samples were analyzed using NMR spectroscopy, with principal components analysis (PCA) followed by partial least squares and orthogonal partial least squares discriminant analyses (PLS-DA and OPLS-DA) used as supervised classification methods. Multivariate data analyses clearly highlighted an adaptation period characterized by an increase in the levels of circulating glutamine and lipids, mobilized to supply the body energy needs. At the same time, a reduction in the circulating levels of glutamate and N-acetyl glycoproteins, stress condition indicators, and proinflammatory markers were also found in the NMR data investigation. Subsequent pathway analysis showed possible perturbations in metabolic processes, potentially related to the physiological adaptation, predominantly found by comparing the baseline (at sea level, before mission onset), the base arrival, and the mission ending collected values. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

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13 pages, 1655 KiB

Open AccessArticle

Muscle Lipid Oxidation Is Not Affected by Obstructive Sleep Apnea in Diabetes and Healthy Subjects

by Zuzana Lattova, Lucie Slovakova, Andrea Plihalova, Jan Gojda, Moustafa Elkalaf, Katerina Westlake and Jan Polak

Int. J. Mol. Sci. 2023, 24(6), 5308; https://doi.org/10.3390/ijms24065308 - 10 Mar 2023

Viewed by 1853

Abstract

The molecular mechanisms linking obstructive sleep apnea (OSA) with type 2 diabetes mellitus (T2DM) remain unclear. This study investigated the effect of OSA on skeletal muscle lipid oxidation in nondiabetic controls and in type 2 diabetes (T2DM) patients. Forty-four participants matched for age and adiposity were enrolled: nondiabetic controls (control, n = 14), nondiabetic patients with severe OSA (OSA, n = 9), T2DM patients with no OSA (T2DM, n = 10), and T2DM patients with severe OSA (T2DM + OSA, n = 11). A skeletal muscle biopsy was performed; gene and protein expressions were determined and lipid oxidation was analyzed. An intravenous glucose tolerance test was performed to investigate glucose homeostasis. No differences in lipid oxidation (178.2 ± 57.1, 161.7 ± 22.4, 169.3 ± 50.9, and 140.0 ± 24.1 pmol/min/mg for control, OSA, T2DM, and T2DM+OSA, respectively; p > 0.05) or gene and protein expressions were observed between the groups. The disposition index, acute insulin response to glucose, insulin resistance, plasma insulin, glucose, and HBA₁C progressively worsened in the following order: control, OSA, T2DM, and T2DM + OSA (p for trend <0.05). No association was observed between the muscle lipid oxidation and the glucose metabolism variables. We conclude that severe OSA is not associated with reduced muscle lipid oxidation and that metabolic derangements in OSA are not mediated through impaired muscle lipid oxidation. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

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15 pages, 3794 KiB

Open AccessArticle

Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry

by Eugenia Mata-Greenwood, Hans C. A. Westenburg, Stacy Zamudio, Nicholas P. Illsley and Lubo Zhang

Int. J. Mol. Sci. 2023, 24(4), 3389; https://doi.org/10.3390/ijms24043389 - 8 Feb 2023

Cited by 1 | Viewed by 2144

Abstract

High-altitude hypoxia challenges reproduction; particularly in non-native populations. Although high-altitude residence is associated with vitamin D deficiency, the homeostasis and metabolism of vitamin D in natives and migrants remain unknown. We report that high altitude (3600 m residence) negatively impacted vitamin D levels, with the high-altitude Andeans having the lowest 25-OH-D levels and the high-altitude Europeans having the lowest 1α,25-(OH)₂-D levels. There was a significant interaction of genetic ancestry with altitude in the ratio of 1α,25-(OH)₂-D to 25-OH-D; with the ratio being significantly lower in Europeans compared to Andeans living at high altitude. Placental gene expression accounted for as much as 50% of circulating vitamin D levels, with CYP2R1 (25-hydroxylase), CYP27B1 (1α-hydroxylase), CYP24A1 (24-hydroxylase), and LRP2 (megalin) as the major determinants of vitamin D levels. High-altitude residents had a greater correlation between circulating vitamin D levels and placental gene expression than low-altitude residents. Placental 7-dehydrocholesterol reductase and vitamin D receptor were upregulated at high altitude in both genetic-ancestry groups, while megalin and 24-hydroxylase were upregulated only in Europeans. Given that vitamin D deficiency and decreased 1α,25-(OH)₂-D to 25-OH-D ratios are associated with pregnancy complications, our data support a role for high-altitude-induced vitamin D dysregulation impacting reproductive outcomes, particularly in migrants. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

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21 pages, 5099 KiB

Open AccessArticle

Small Extracellular Vesicles from Hypoxic Triple-Negative Breast Cancer Cells Induce Oxygen-Dependent Cell Invasion

by Bianca Cruz Pachane, Ana Carolina Caetano Nunes, Thais Regiani Cataldi, Kelli Cristina Micocci, Bianca Caruso Moreira, Carlos Alberto Labate, Heloisa Sobreiro Selistre-de-Araujo and Wanessa Fernanda Altei

Int. J. Mol. Sci. 2022, 23(20), 12646; https://doi.org/10.3390/ijms232012646 - 21 Oct 2022

Cited by 8 | Viewed by 2566

Abstract

Hypoxia, a condition of low oxygenation frequently found in triple-negative breast tumors (TNBC), promotes extracellular vesicle (EV) secretion and favors cell invasion, a complex process in which cell morphology is altered, dynamic focal adhesion spots are created, and ECM is remodeled. Here, we investigated the invasive properties triggered by TNBC-derived hypoxic small EV (SEVh) in vitro in cells cultured under hypoxic (1% O₂) and normoxic (20% O₂) conditions, using phenotypical and proteomic approaches. SEVh characterization demonstrated increased protein abundance and diversity over normoxic SEV (SEVn), with enrichment in pro-invasive pathways. In normoxic cells, SEVh promotes invasive behavior through pro-migratory morphology, invadopodia development, ECM degradation, and matrix metalloprotease (MMP) secretion. The proteome profiling of 20% O₂-cultured cells exposed to SEVh determined enrichment in metabolic processes and cell cycles, modulating cell health to escape apoptotic pathways. In hypoxia, SEVh was responsible for proteolytic and catabolic pathway inducement, interfering with integrin availability and gelatinase expression. Overall, our results demonstrate the importance of hypoxic signaling via SEV in tumors for the early establishment of metastasis. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

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15 pages, 1955 KiB

Open AccessArticle

Fertility Impairment after Trekking at High Altitude: A Proof of Mechanisms on Redox and Metabolic Seminal Changes

by Vittore Verratti, Simona Mrakic-Sposta, Jonathan Fusi, Iva Sabovic, Ferdinando Franzoni, Tiziana Pietrangelo, Danilo Bondi, Stefano Dall’Acqua, Simona Daniele, Giorgia Scarfò, Camillo Di Giulio and Andrea Garolla

Int. J. Mol. Sci. 2022, 23(16), 9066; https://doi.org/10.3390/ijms23169066 - 13 Aug 2022

Cited by 7 | Viewed by 2625

Abstract

Many authors described negative but reversible effects of high-altitude hypoxic exposure on animal and human fertility in terms of sperm concentration, function, and biochemical alterations. The aim of this study was to evaluate the acute and chronic effects of high-altitude exposure on classical sperm parameters, redox status, and membrane composition in a group of travellers. Five healthy Italian males, all lowlanders not accustomed to the altitude, were evaluated after 19 days-trekking through low, moderate, and high altitudes in the Himalayas. Sperm samples were collected before (Pre), 10 days after (Post), and 70 days after the end of the expedition (Follow-up). Sperm concentration, cholesterol and oxysterol membrane content, and redox status were measured. Hypoxic trek led to a significant reduction in sperm concentration (p < 0.001, η²p = 0.91), with a reduction from Pre to Post (71.33 ± 38.81 to 60.65 ± 34.63 × 10⁶/mL) and a further reduction at Follow-up (to 37.13 ± 39.17 × 10⁶/mL). The seminal volume was significantly affected by the hypoxic trek (p = 0.001, η²p = 0.75) with a significant reduction from Pre to Post (2.86 ± 0.75 to 1.68 ± 0.49 mL) and with partial recovery at Follow-up (to 2.46 ± 0.45 mL). Moreover, subjects had an increase in ROS production (+86%), and a decrease in antioxidant capacity (−37%) in the Post period with partial recovery at Follow-up. These results integrated the hormonal response on thyroid function, hypothalamus–pituitary–gonadal axis, and the prolactin/cortisol pathways previously reported. An uncontrolled ROS production, rather than a compromised antioxidant activity, was likely the cause of impaired sperm quality. The reduction in fertility status observed in this study may lie in an evolutionary Darwinian explanation, i.e., limiting reproduction due to the “adaptive disadvantage” offered by the combined stressors of high-altitude hypoxia and daily physical exercise. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

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Review

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25 pages, 1186 KiB

Open AccessReview

The Brain at High Altitude: From Molecular Signaling to Cognitive Performance

by Mostafa A. Aboouf, Markus Thiersch, Jorge Soliz, Max Gassmann and Edith M. Schneider Gasser

Int. J. Mol. Sci. 2023, 24(12), 10179; https://doi.org/10.3390/ijms241210179 - 15 Jun 2023

Cited by 6 | Viewed by 6779

Abstract

The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

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15 pages, 2400 KiB

Open AccessReview

Molecular Regulation of the Response of Brain Pericytes to Hypoxia

by Robert Carlsson, Andreas Enström and Gesine Paul

Int. J. Mol. Sci. 2023, 24(6), 5671; https://doi.org/10.3390/ijms24065671 - 16 Mar 2023

Cited by 7 | Viewed by 2881

Abstract

The brain needs sufficient oxygen in order to function normally. This is achieved by a large vascular capillary network ensuring that oxygen supply meets the changing demand of the brain tissue, especially in situations of hypoxia. Brain capillaries are formed by endothelial cells and perivascular pericytes, whereby pericytes in the brain have a particularly high 1:1 ratio to endothelial cells. Pericytes not only have a key location at the blood/brain interface, they also have multiple functions, for example, they maintain blood–brain barrier integrity, play an important role in angiogenesis and have large secretory abilities. This review is specifically focused on both the cellular and the molecular responses of brain pericytes to hypoxia. We discuss the immediate early molecular responses in pericytes, highlighting four transcription factors involved in regulating the majority of transcripts that change between hypoxic and normoxic pericytes and their potential functions. Whilst many hypoxic responses are controlled by hypoxia-inducible factors (HIF), we specifically focus on the role and functional implications of the regulator of G-protein signaling 5 (RGS5) in pericytes, a hypoxia-sensing protein that is regulated independently of HIF. Finally, we describe potential molecular targets of RGS5 in pericytes. These molecular events together contribute to the pericyte response to hypoxia, regulating survival, metabolism, inflammation and induction of angiogenesis. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

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38 pages, 3550 KiB

Open AccessReview

The Oxygen Cascade from Atmosphere to Mitochondria as a Tool to Understand the (Mal)adaptation to Hypoxia

by Michele Samaja and Sara Ottolenghi

Int. J. Mol. Sci. 2023, 24(4), 3670; https://doi.org/10.3390/ijms24043670 - 12 Feb 2023

Cited by 5 | Viewed by 3883

Abstract

Hypoxia is a life-threatening challenge for about 1% of the world population, as well as a contributor to high morbidity and mortality scores in patients affected by various cardiopulmonary, hematological, and circulatory diseases. However, the adaptation to hypoxia represents a failure for a relevant portion of the cases as the pathways of potential adaptation often conflict with well-being and generate diseases that in certain areas of the world still afflict up to one-third of the populations living at altitude. To help understand the mechanisms of adaptation and maladaptation, this review examines the various steps of the oxygen cascade from the atmosphere to the mitochondria distinguishing the patterns related to physiological (i.e., due to altitude) and pathological (i.e., due to a pre-existing disease) hypoxia. The aim is to assess the ability of humans to adapt to hypoxia in a multidisciplinary approach that correlates the function of genes, molecules, and cells with the physiologic and pathological outcomes. We conclude that, in most cases, it is not hypoxia by itself that generates diseases, but rather the attempts to adapt to the hypoxia condition. This underlies the paradigm shift that when adaptation to hypoxia becomes excessive, it translates into maladaptation. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

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29 pages, 1889 KiB

Open AccessReview

Molecular Mechanisms of High-Altitude Acclimatization

by Robert T. Mallet, Johannes Burtscher, Vincent Pialoux, Qadar Pasha, Yasmin Ahmad, Grégoire P. Millet and Martin Burtscher

Int. J. Mol. Sci. 2023, 24(2), 1698; https://doi.org/10.3390/ijms24021698 - 15 Jan 2023

Cited by 43 | Viewed by 14235

Abstract

High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

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