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Special Issue "Adaptation to Hypoxia: A Chimera?"

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

Deadline for manuscript submissions: closed (25 September 2019).

Special Issue Editors

Prof. Dr. Michele Samaja
E-Mail Website
Guest Editor
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
Special Issues and Collections in MDPI journals
Dr. Giuseppina Milano
E-Mail Website
Guest Editor
Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland
Interests: chronic hypoxia; acute myocardial infarction; cardioprotection; hypoxic pulmonary hypertension; ischemia reperfusion injury; cardiac regeneration; cardiotoxicity; echocardiography; animal models
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

The Chimera was, according to Greek mythology, a monstrous fire-breathing hybrid creature of Lycia in Asia Minor, composed of the parts of more than one animal. Hence, the term "chimera" has come to describe anything composed of very disparate parts, or perceived as wildly imaginative, implausible, or dazzling (adapted from Wikipedia).

A world-relevant clinical and environment issue that affects millions of people, hypoxia, i.e., the insufficient supply of oxygen with respect to demand, constitutes an important source of social and economic distress. Despite hypoxia representing a potentially lethal condition, the human body possesses reserves that enable the recruitment of defense mechanisms to grant survival during relatively acute episodes. Clearly, however, when sustained or chronic, hypoxia is predicted to request a greater effort to balance its harmful effects, despite a longer time allowed to recruit gene-based and proteomic compensatory mechanisms. Chronic exposure to stressors, however, implies the concept of adaptation, or the “modification of an organism or its parts that makes it more fit for existence under the conditions of its environment: a heritable physical or behavioral trait that serves a specific function and improves an organism's fitness or survival” (Merriam-Webster Dictionary). Because at least some of the biological systems that constitute complex living matter have limited regenerative capacity, such as the cerebral and cardiopulmonary systems, the concept of adaptation is, therefore, particularly relevant, but several unanswered undeveloped questions, arise:

  1. How can we assess the onset of adaptation? In other words, which physiological (e.g., blunted erythropoiesis, control of alkalemia due to excess ventilation, recovery of body’s homeostasis), molecular (e.g., normalization of NO stores, recruitment of hypoxia-sensitive genes and proteins), pathological (e.g., weight at birth, resistance against cardiopulmonary diseases, integrity of the cerebral function) best represent a target of adaptation?
  2. Does adaptation invest the whole body or can some organs/functions become better or faster adapted than others? This question may be linked to other important sub-questions: (1) Why are some populations better adapted than others, for example, Tibetan vs. South American dwellers? (2) How do Ethiopians, Kirgiz, long-term inhabitants of the Antarctica rank with respect to the mentioned Tibetan and South Americans dwellers? (3) Why do comparable degrees of hypoxia in some categories of patients lead to deleterious consequences, for example, blue babies and patients with COPD or pulmonary hypertension?
  3. Sometimes, high-altitude people opt to reside at lower altitudes. Can adaptation work in a reverse mode by enabling altitude-adapted people to survive relatively oxygen-rich atmospheres?
  4. Is adaptation always a positive factor, or are there instances where adaptation, or better maladaptation, might lead to deleterious patterns?
  5. Are factors such as the degree of activity, intermittent exposure to different oxygen levels, and life habits critical to enabling better and faster adaptation? Is there a role for the hypoxia-induced oxidative stress in these patterns?
  6. Is the classical HIF-1a pathway sufficient to explain the complexity of the responses to chronic hypoxia and to enable adaptive patterns?
  7. Are appropriate biomarkers available to assess the degree of adaptation, or the lack of adaptation to hypoxia?

We believe that answering these questions may enable us to understand whether humans, who underwent a genetical selection as a low-altitude population, may ever be able to adapt to either environmental or pathological hypoxia, or if hypoxia adaptation is and will remain a chimera.

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

Manuscript Submission Information

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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

Published Papers (5 papers)

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Research

Open AccessArticle
The Fast Lane of Hypoxic Adaptation: Glucose Transport Is Modulated via A HIF-Hydroxylase-AMPK-Axis in Jejunum Epithelium
Int. J. Mol. Sci. 2019, 20(20), 4993; https://doi.org/10.3390/ijms20204993 - 09 Oct 2019
Abstract
The intestinal epithelium is able to adapt to varying blood flow and, thus, oxygen availability. Still, the adaptation fails under pathologic situations. A better understanding of the mechanisms underlying the epithelial adaptation to hypoxia could help to improve the therapeutic approach. We hypothesized [...] Read more.
The intestinal epithelium is able to adapt to varying blood flow and, thus, oxygen availability. Still, the adaptation fails under pathologic situations. A better understanding of the mechanisms underlying the epithelial adaptation to hypoxia could help to improve the therapeutic approach. We hypothesized that the short-term adaptation to hypoxia is mediated via AMP-activated protein kinase (AMPK) and that it is coupled to the long-term adaptation by a common regulation mechanism, the HIF-hydroxylase enzymes. Further, we hypothesized the transepithelial transport of glucose to be part of this short-term adaptation. We conducted Ussing chamber studies using isolated lagomorph jejunum epithelium and cell culture experiments with CaCo-2 cells. The epithelia and cells were incubated under 100% and 21% O2, respectively, with the panhydroxylase inhibitor dimethyloxalylglycine (DMOG) or under 1% O2. We showed an activation of AMPK under hypoxia and after incubation with DMOG by Western blot. This could be related to functional effects like an impairment of Na+-coupled glucose transport. Inhibitor studies revealed a recruitment of glucose transporter 1 under hypoxia, but not after incubation with DMOG. Summing up, we showed an influence of hydroxylase enzymes on AMPK activity and similarities between hypoxia and the effects of hydroxylase inhibition on functional changes. Full article
(This article belongs to the Special Issue Adaptation to Hypoxia: A Chimera?)
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Open AccessArticle
Radical Stress Is More Cytotoxic in the Nucleus than in Other Organelles
Int. J. Mol. Sci. 2019, 20(17), 4147; https://doi.org/10.3390/ijms20174147 - 25 Aug 2019
Abstract
Cells are exposed to reactive oxygen species (ROS) as a by-product of mitochondrial metabolism, especially under hypoxia. ROS are also enzymatically generated at the plasma membrane during inflammation. Radicals cause cellular damage leading to cell death, as they react indiscriminately with surrounding lipids, [...] Read more.
Cells are exposed to reactive oxygen species (ROS) as a by-product of mitochondrial metabolism, especially under hypoxia. ROS are also enzymatically generated at the plasma membrane during inflammation. Radicals cause cellular damage leading to cell death, as they react indiscriminately with surrounding lipids, proteins, and nucleotides. However, ROS are also important for many physiological processes, including signaling, pathogen killing and chemotaxis. The sensitivity of cells to ROS therefore likely depends on the subcellular location of ROS production, but how this affects cell viability is poorly understood. As ROS generation consumes oxygen, and hypoxia-mediated signaling upregulates expression of antioxidant transcription factor Nrf2, it is difficult to discern hypoxic from radical stress. In this study, we developed an optogenetic toolbox for organelle-specific generation of ROS using the photosensitizer protein SuperNova which produces superoxide anion upon excitation with 590 nm light. We fused SuperNova to organelle specific localization signals to induce ROS with high precision. Selective ROS production did not affect cell viability in most organelles except for the nucleus. SuperNova is a promising tool to induce locally targeted ROS production, opening up new possibilities to investigate processes and organelles that are affected by localized ROS production. Full article
(This article belongs to the Special Issue Adaptation to Hypoxia: A Chimera?)
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Open AccessArticle
Regulation of Serum Sphingolipids in Andean Children Born and Living at High Altitude (3775 m)
Int. J. Mol. Sci. 2019, 20(11), 2835; https://doi.org/10.3390/ijms20112835 - 11 Jun 2019
Abstract
Recent studies on Andean children indicate a prevalence of dyslipidemia and hypertension compared to dwellers at lower altitudes, suggesting that despite similar food intake and daily activities, they undergo different metabolic adaptations. In the present study, the sphingolipid pattern was investigated in serum [...] Read more.
Recent studies on Andean children indicate a prevalence of dyslipidemia and hypertension compared to dwellers at lower altitudes, suggesting that despite similar food intake and daily activities, they undergo different metabolic adaptations. In the present study, the sphingolipid pattern was investigated in serum of 7 underweight (UW), 30 normal weight (NW), 13 overweight (OW), and 9 obese (O) Andean children by liquid chromatography-mass spectrometry (LC-MS). Results indicate that levels of Ceramides (Cers) and sphingomyelins (SMs) correlate positively with biochemical parameters (except for Cers and Vitamin D, which correlate negatively), whereas sphingosine-1-phosphate (S1P) correlates negatively. Correlation results and LC-MS data identify the axis high density lipoprotein-cholesterol (HDL-C), Cers, and S1P as related to hypoxia adaptation. Specifically UW children are characterized by increased levels of S1P compared to O and lower levels of Cers compared to NW children. Furthermore, O children show lower levels of S1P and similar levels of Cers and SMs as NW. In conclusion, our results indicate that S1P is the primary target of hypoxia adaptation in Andean children, and its levels are associated with hypoxia tolerance. Furthermore, S1P can act as marker of increased risk of metabolic syndrome and cardiac dysfunction in young Andeans living at altitude. Full article
(This article belongs to the Special Issue Adaptation to Hypoxia: A Chimera?)
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Open AccessArticle
Adaptive Changes of Glioblastoma Cells Following Exposure to Hypoxic (1% Oxygen) Tumour Microenvironment
Int. J. Mol. Sci. 2019, 20(9), 2091; https://doi.org/10.3390/ijms20092091 - 28 Apr 2019
Abstract
Glioblastoma multiforme is the most aggressive and malignant primary brain tumour, with a median survival rate of between 15 to 17 months. Heterogeneous regions occur in glioblastoma as a result of oxygen gradients which ranges from 0.1% to 10% in vivo. Emerging evidence [...] Read more.
Glioblastoma multiforme is the most aggressive and malignant primary brain tumour, with a median survival rate of between 15 to 17 months. Heterogeneous regions occur in glioblastoma as a result of oxygen gradients which ranges from 0.1% to 10% in vivo. Emerging evidence suggests that tumour hypoxia leads to increased aggressiveness and chemo/radio resistance. Yet, few in vitro studies have been performed in hypoxia. Using three glioblastoma cell-lines (U87, U251, and SNB19), the adaptation of glioblastoma cells in a 1% (hypoxia) and 20% (normoxia) oxygen microenvironment on proliferation, metabolism, migration, neurosphere formation, CD133 and VEGF expression was investigated. Compared to cells maintained in normoxia (20% oxygen), glioblastoma cells adapted to 1% oxygen tension by reducing proliferation and enhancing metabolism. Both migratory tendency and neurosphere formation ability were greatly limited. In addition, hypoxic-mediated gene upregulation (CD133 and VEGF) was reversed when cells were removed from the hypoxic environment. Collectively, our results reveal that hypoxia plays a pivotal role in changing the behaviour of glioblastoma cells. We have also shown that genetic modulation can be reversed, supporting the concept of reversibility. Thus, understanding the degree of oxygen gradient in glioblastoma will be crucial in personalising treatment for glioblastoma patients. Full article
(This article belongs to the Special Issue Adaptation to Hypoxia: A Chimera?)
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Open AccessArticle
Identification and Characterization of Four Autophagy-Related Genes That Are Expressed in Response to Hypoxia in the Brain of the Oriental River Prawn (Macrobrachium nipponense)
Int. J. Mol. Sci. 2019, 20(8), 1856; https://doi.org/10.3390/ijms20081856 - 15 Apr 2019
Abstract
Autophagy is a cytoprotective mechanism triggered in response to adverse environmental conditions. Herein, we investigated the autophagy process in the oriental river prawn (Macrobrachium nipponense) following hypoxia. Full-length cDNAs encoding autophagy-related genes (ATGs) ATG3, ATG4B, ATG5, and ATG9A [...] Read more.
Autophagy is a cytoprotective mechanism triggered in response to adverse environmental conditions. Herein, we investigated the autophagy process in the oriental river prawn (Macrobrachium nipponense) following hypoxia. Full-length cDNAs encoding autophagy-related genes (ATGs) ATG3, ATG4B, ATG5, and ATG9A were cloned, and transcription following hypoxia was explored in different tissues and developmental stages. The ATG3, ATG4B, ATG5, and ATG9A cDNAs include open reading frames encoding proteins of 319, 264, 268, and 828 amino acids, respectively. The four M. nipponense proteins clustered separately from vertebrate homologs in phylogenetic analysis. All four mRNAs were expressed in various tissues, with highest levels in brain and hepatopancreas. Hypoxia up-regulated all four mRNAs in a time-dependent manner. Thus, these genes may contribute to autophagy-based responses against hypoxia in M. nipponense. Biochemical analysis revealed that hypoxia stimulated anaerobic metabolism in the brain tissue. Furthermore, in situ hybridization experiments revealed that ATG4B was mainly expressed in the secretory and astrocyte cells of the brain. Silencing of ATG4B down-regulated ATG8 and decreased cell viability in juvenile prawn brains following hypoxia. Thus, autophagy is an adaptive response protecting against hypoxia in M. nipponense and possibly other crustaceans. Recombinant MnATG4B could interact with recombinant MnATG8, but the GST protein could not bind to MnATG8. These findings provide us with a better understanding of the fundamental mechanisms of autophagy in prawns. Full article
(This article belongs to the Special Issue Adaptation to Hypoxia: A Chimera?)
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