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      Differences in Tolerance to Hypoxia: Physiological, Biochemical, and Molecular-Biological Characteristics

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          Abstract

          Hypoxia plays an important role in the development of many infectious, inflammatory, and tumor diseases. The predisposition to such disorders is mostly provided by differences in basic tolerance to oxygen deficiency, which we discuss in this review. Except the direct exposure of different-severity hypoxia in decompression chambers or in highland conditions, there are no alternative methods for determining organism tolerance. Due to the variability of the detection methods, differences in many parameters between tolerant and susceptible organisms are still not well-characterized, but some of them can serve as biomarkers of susceptibility to hypoxia. At the moment, several potential biomarkers in conditions after hypoxic exposure have been identified both in experimental animals and humans. The main potential biomarkers are Hypoxia-Inducible Factor (HIF)-1, Heat-Shock Protein 70 (HSP70), and NO. Due to the different mechanisms of various high-altitude diseases, biomarkers may not be highly specific and universal. Therefore, it is extremely important to conduct research on hypoxia susceptibility biomarkers. Moreover, it is important to develop a method for the evaluation of organisms’ basic hypoxia tolerance without the necessity of any oxygen deficiency exposure. This can contribute to new personalized medicine approaches’ development for diagnostics and the treatment of inflammatory and tumor diseases, taking into account hypoxia tolerance differences.

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          Most cited references230

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          Hypoxia-inducible factors in physiology and medicine.

          Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology. The hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis in all metazoan species. Rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of HIF dysregulation in chronic diseases, and investigating potential targeting of HIFs for therapeutic purposes. Copyright © 2012 Elsevier Inc. All rights reserved.
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            A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.

            We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.
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              Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.

              Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.
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                Author and article information

                Journal
                Biomedicines
                Biomedicines
                biomedicines
                Biomedicines
                MDPI
                2227-9059
                18 October 2020
                October 2020
                : 8
                : 10
                : 428
                Affiliations
                Department of Immunomorphology of Inflammation, Federal State Budgetary Institution ‘Research Institute of Human Morphology’, Moscow 117418, Russia; makarov.olga2013@ 123456yandex.ru
                Author notes
                [* ]Correspondence: juliajal93@ 123456mail.ru ; Tel.: +7-499-128-96-82
                Author information
                https://orcid.org/0000-0002-1337-7160
                Article
                biomedicines-08-00428
                10.3390/biomedicines8100428
                7603118
                33080959
                6cb7bcea-e59b-4799-ad58-4e6bcfce0a04
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 September 2020
                : 15 October 2020
                Categories
                Review

                tolerance to hypoxia,high altitude,biomarkers,hypoxia-inducible factor,acute mountain sickness,high-altitude pulmonary edema

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