scholarly journals Hypoxia and Inflammation: Insights From High-Altitude Physiology

2021 ◽  
Vol 12 ◽  
Author(s):  
Kathy Pham ◽  
Keval Parikh ◽  
Erica C. Heinrich
Keyword(s):  
High Altitude ◽  
Immune Function ◽  
Immune Cell ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Human Populations ◽  
Inflammatory Signaling ◽  
Time Domains ◽  
Inflammatory Phenotypes ◽  
Hif Pathway

The key regulators of the transcriptional response to hypoxia and inflammation (hypoxia inducible factor, HIF, and nuclear factor-kappa B, NF-κB, respectively) are evolutionarily conserved and share significant crosstalk. Tissues often experience hypoxia and inflammation concurrently at the site of infection or injury due to fluid retention and immune cell recruitment that ultimately reduces the rate of oxygen delivery to tissues. Inflammation can induce activity of HIF-pathway genes, and hypoxia may modulate inflammatory signaling. While it is clear that these molecular pathways function in concert, the physiological consequences of hypoxia-induced inflammation and how hypoxia modulates inflammatory signaling and immune function are not well established. In this review, we summarize known mechanisms of HIF and NF-κB crosstalk and highlight the physiological consequences that can arise from maladaptive hypoxia-induced inflammation. Finally, we discuss what can be learned about adaptive regulation of inflammation under chronic hypoxia by examining adaptive and maladaptive inflammatory phenotypes observed in human populations at high altitude. We aim to provide insight into the time domains of hypoxia-induced inflammation and highlight the importance of hypoxia-induced inflammatory sensitization in immune function, pathologies, and environmental adaptation.

scholarly journals High altitude adaptation mitigates anemia risk associated with diabetes among the Mosuo of Southwest China

2018 ◽  
Author(s):  
M Su ◽  
K Wander ◽  
MK Shenk ◽  
T Blumenfield ◽  
H Li ◽  
...  
Keyword(s):  
Tibetan Plateau ◽  
High Altitude ◽  
Market Integration ◽  
Hypoxia Inducible Factor ◽  
Human Populations ◽  
The Tibetan Plateau ◽  
Low Oxygen ◽  
High Altitude Adaptation ◽  
Altitude Adaptation ◽  
Hb Concentration

AbstractHuman populations native to high altitude regions (≥2500 m) exhibit numerous adaptations to hypoxic stress. On the Tibetan Plateau, these include modifications of the hypoxia inducible factor (HIF) pathway to essentially uncouple erythropoiesis (red blood cell production) and blood hemoglobin (Hb) concentration—which normally increase in response to low oxygen—from hypoxia. Uncoupling of erythropoiesis and hypoxia is also observed among people with diabetes due to damage to kidney tissues. This is hypothesized to result in elevated risk for anemia among diabetics, which increases risk for cardiovascular disease and death. We tested the hypothesis that the independence of erythropoiesis from HIF among high-altitude adapted populations of the Tibetan Plateau may protect against diabetes-associated anemia. We investigated this hypothesis among the Mosuo, a population living in Yunnan Province, China (at ~2800 m altitude) that is undergoing rapid market integration and lifestyle change, with concomitant increase in risk for type 2 diabetes. We found that, although diabetes (glycated hemoglobin, HbA1c ≥6.5%) is associated with anemia (females: Hb<12g/dl; males: Hb<13g/dl) among the Chinese population as a whole (N: 5,606; OR: 1.48; p: 0.008), this is not the case among the Mosuo (N: 316; OR: 1.36; p: 0.532). Both pathways uncoupling hypoxia from erythropoiesis (diabetic disease and high altitude adaptation) are incompletely understood; their intersection in protecting Mosuo with diabetes from anemia may provide insight into the mechanisms underlying each. Further, these findings point to the importance of understanding how high-altitude adaptations interact with chronic disease processes, as populations like the Mosuo experience rapid market integration.

Ancient Atmospheres and the Evolution of Oxygen Sensing Via the Hypoxia-Inducible Factor in Metazoans

Physiology ◽  
2010 ◽  
Vol 25 (5) ◽  
pp. 272-279 ◽  
Author(s):  
Cormac T. Taylor ◽  
Jennifer C. McElwain
Keyword(s):  
Oxygen Sensing ◽  
Atmospheric Oxygen ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Oxygen Levels ◽  
Selection Force ◽  
Cellular Oxygen ◽  
Hif Pathway ◽  
Evolution Of Oxygen ◽  
Oxygen Concentrations

Metazoan diversification occurred during a time when atmospheric oxygen levels fluctuated between 15 and 30%. The hypoxia-inducible factor (HIF) is a primary regulator of the adaptive transcriptional response to hypoxia. Although the HIF pathway is highly conserved, its complexity increased during periods when atmospheric oxygen concentrations were increasing. Thus atmospheric oxygen levels may have provided a selection force on the development of cellular oxygen-sensing pathways.

scholarly journals Hypoxia and inflammation

2017 ◽  
Vol 39 (4) ◽  
pp. 34-36 ◽  
Author(s):  
Eoin P. Cummins ◽  
Cormac T. Taylor
Keyword(s):  
Inflammatory Bowel Disease ◽  
Cell Function ◽  
Immune Cell ◽  
Hypoxia Inducible Factor ◽  
Oxygen Demand ◽  
Chronic Inflammatory Disease ◽  
Immune Cell Function ◽  
Inflammatory Bowel ◽  
Transcriptional Pathway ◽  
Hif Pathway

Uncontrolled or non-resolving inflammation is central to the pathophysiology of clinically important conditions including inflammatory bowel disease (IBD), psoriasis, atherosclerosis and arthritis. A combination of increased oxygen demand and decreased supply renders the local microenvironment of chronically inflamed tissues oxygen deprived (hypoxic), leading to the expression of a programme of genes that promote adaptation to the hypoxic challenge. This ancient and ubiquitous adaptive transcriptional pathway is governed by a transcription factor termed the hypoxia-inducible factor (HIF). Originally identified in the search for regulators of hypoxia-induced erythropoietin expression and adaptation to high altitude, HIF has been more recently recognized as a major regulator of immune cell function, which is central to the control of immunity and inflammation. Indeed, recent studies have demonstrated that the use of drugs targeting the HIF pathway may be of benefit in the treatment of chronic inflammatory disease.

scholarly journals High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

2021 ◽  
Author(s):  
Jay F Storz
Keyword(s):  
High Altitude ◽  
Hypoxia Inducible Factor ◽  
Feedback Regulation ◽  
Genomic Analyses ◽  
Manipulative Experiments ◽  
Altitude Adaptation ◽  
Mechanisms Of Adaptation ◽  
Physiological Pathways ◽  
Underlying Mechanisms ◽  
Integrated Genomics

AbstractPopulation genomic analyses of high-altitude humans and other vertebrates have identified numerous candidate genes for hypoxia adaptation, and the physiological pathways implicated by such analyses suggest testable hypotheses about underlying mechanisms. Studies of highland natives that integrate genomic data with experimental measures of physiological performance capacities and subordinate traits are revealing associations between genotypes (e.g., hypoxia-inducible factor gene variants) and hypoxia-responsive phenotypes. The subsequent search for causal mechanisms is complicated by the fact that observed genotypic associations with hypoxia-induced phenotypes may reflect second-order consequences of selection-mediated changes in other (unmeasured) traits that are coupled with the focal trait via feedback regulation. Manipulative experiments to decipher circuits of feedback control and patterns of phenotypic integration can help identify causal relationships that underlie observed genotype–phenotype associations. Such experiments are critical for correct inferences about phenotypic targets of selection and mechanisms of adaptation.

scholarly journals Hypoxia-Inducible Factor 2a Expression Is Positively Correlated With Gleason Score in Prostate Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382199001
Author(s):  
Dimitrios Pavlakis ◽  
Spyridon Kampantais ◽  
Konstantinos Gkagkalidis ◽  
Victoras Gourvas ◽  
Dimitrios Memmos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gleason Score ◽  
Locally Advanced ◽  
Hypoxia Inducible Factor ◽  
Immunohistochemical Expression ◽  
Locally Advanced Prostate Cancer ◽  
Grade Group ◽  
Main Factors ◽  
Hif Pathway ◽  
Lower Expression

Background: One of the main factors in response to hypoxia in the tumor microenvironment is the hypoxia-inducible factor (HIF) pathway. Although its role in other solid tumors, particularly renal cell carcinoma, has been sufficiently elucidated, it remains elusive in prostate cancer. The aim of the present study was to investigate the expression of main proteins involved in this pathway and determine the correlation of the results with clinicopathological outcomes of patients with prostate cancer. Methods: The immunohistochemical expression of HIF-1a, HIF-2a and their regulators, prolyl hydroxylase domain (PHD)1, PHD2 and PHD3 and factor inhibiting HIF (FIH), was assessed on a tissue microarray. This was constructed from radical prostatectomy specimens, involving both tumor and corresponding adjacent non-tumoral prostate tissues from 50 patients with localized or locally advanced prostate cancer. Results: In comparison with non-tumoral adjacent tissue, HIF-1a exhibited an equal or lower expression in 86% of the specimens (P = 0.017), while HIF-2a was overexpressed in 52% (P = 0.032) of the cases. HIF-1a protein expression was correlated with HIF-2a (P < 0.001), FIH (P = 0.004), PHD1 (P < 0.001), PHD2 (P < 0.001) and PHD3 (P = 0.035). HIF-2a expression was positively correlated with Gleason score (P = 0.017) and International Society of Urological Pathologists (ISUP) grade group (P = 0.022). Conclusions: The findings of the present study suggest a key role for HIF-2a in prostate cancer, as HIF-2a expression was found to be correlated with Gleason score and ISUP grade of the patients. However, further studies are required to validate these results and investigate the potential value of HIF-2a as a therapeutic target in prostate cancer.

scholarly journals Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival

Oncogene ◽  
2014 ◽  
Vol 34 (34) ◽  
pp. 4482-4490 ◽  
Author(s):  
H Choudhry ◽  
A Albukhari ◽  
M Morotti ◽  
S Haider ◽  
D Moralli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Transcriptional Activation ◽  
Cellular Proliferation ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Transcriptional Response ◽  
Clonogenic Survival ◽  
Breast Cancer Cell Lines ◽  
Transcriptional Responses

Abstract Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.

HIF-1α in endurance training: suppression of oxidative metabolism

2007 ◽  
Vol 293 (5) ◽  
pp. R2059-R2069 ◽  
Author(s):  
Steven D. Mason ◽  
Helene Rundqvist ◽  
Ioanna Papandreou ◽  
Roger Duh ◽  
Wayne J. McNulty ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Training ◽  
Oxidative Metabolism ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Oxidative Capacity ◽  
Pyruvate Dehydrogenase Kinase ◽  
Amp Activated Protein Kinase ◽  
Training Protocol

During endurance training, exercising skeletal muscle experiences severe and repetitive oxygen stress. The primary transcriptional response factor for acclimation to hypoxic stress is hypoxia-inducible factor-1α (HIF-1α), which upregulates glycolysis and angiogenesis in response to low levels of tissue oxygenation. To examine the role of HIF-1α in endurance training, we have created mice specifically lacking skeletal muscle HIF-1α and subjected them to an endurance training protocol. We found that only wild-type mice improve their oxidative capacity, as measured by the respiratory exchange ratio; surprisingly, we found that HIF-1α null mice have already upregulated this parameter without training. Furthermore, untrained HIF-1α null mice have an increased capillary to fiber ratio and elevated oxidative enzyme activities. These changes correlate with constitutively activated AMP-activated protein kinase in the HIF-1α null muscles. Additionally, HIF-1α null muscles have decreased expression of pyruvate dehydrogenase kinase I, a HIF-1α target that inhibits oxidative metabolism. These data demonstrate that removal of HIF-1α causes an adaptive response in skeletal muscle akin to endurance training and provides evidence for the suppression of mitochondrial biogenesis by HIF-1α in normal tissue.

The evolutionary and physiological significance of the Hif pathway in teleost fishes

2021 ◽  
Vol 224 (18) ◽  
Author(s):  
Milica Mandic ◽  
William Joyce ◽  
Steve F. Perry
Keyword(s):  
Hypoxia Inducible Factor ◽  
Duplication Event ◽  
Hypoxia Tolerance ◽  
Evolutionary Significance ◽  
Hypoxic Exposure ◽  
Cardiorespiratory System ◽  
Genome Duplication Event ◽  
Hypoxic Response ◽  
Hif Pathway ◽  
The Impact

ABSTRACT The hypoxia-inducible factor (HIF) pathway is a key regulator of cellular O2 homeostasis and an important orchestrator of the physiological responses to hypoxia (low O2) in vertebrates. Fish can be exposed to significant and frequent changes in environmental O2, and increases in Hif-α (the hypoxia-sensitive subunit of the transcription factor Hif) have been documented in a number of species as a result of a decrease in O2. Here, we discuss the impact of the Hif pathway on the hypoxic response and the contribution to hypoxia tolerance, particularly in fishes of the cyprinid lineage, which includes the zebrafish (Danio rerio). The cyprinids are of specific interest because, unlike in most other fishes, duplicated paralogs of the Hif-α isoforms arising from a teleost-specific genome duplication event have been retained. Positive selection has acted on the duplicated paralogs of the Hif-α isoforms in some cyprinid sub-families, pointing to adaptive evolutionary change in the paralogs. Thus, cyprinids are valuable models for exploring the evolutionary significance and physiological impact of the Hif pathway on the hypoxic response. Knockout in zebrafish of either paralog of Hif-1α greatly reduces hypoxia tolerance, indicating the importance of both paralogs to the hypoxic response. Here, with an emphasis on the cardiorespiratory system, we focus on the role of Hif-1α in the hypoxic ventilatory response and the regulation of cardiac function. We explore the effects of the duration of the hypoxic exposure (acute, sustained or intermittent) on the impact of Hif-1α on cardiorespiratory function and compare relevant data with those from mammalian systems.

scholarly journals Variations within oxygen-regulated gene expression in humans

2009 ◽  
Vol 106 (1) ◽  
pp. 212-220 ◽  
Author(s):  
Jerome T. S. Brooks ◽  
Gareth P. Elvidge ◽  
Louisa Glenny ◽  
Jonathan M. Gleadle ◽  
Chun Liu ◽  
...  
Keyword(s):  
Cellular Response ◽  
Genetic Manipulation ◽  
Hypoxia Inducible Factor ◽  
Hereditary Disease ◽  
Peripheral Blood Lymphocytes ◽  
Cellular Level ◽  
Normal Individuals ◽  
Regulated Gene Expression ◽  
Open Question ◽  
Hif Pathway

The effects of hypoxia on gene transcription are mainly mediated by a transcription factor complex termed hypoxia-inducible factor (HIF). Genetic manipulation of animals and studies of humans with rare hereditary disease have shown that modifying the HIF pathway affects systems-level physiological responses to hypoxia. It is, however, an open question whether variations in systems-level responses to hypoxia between individuals could arise from variations within the HIF system. This study sought to determine whether variations in the responsiveness of the HIF system at the cellular level could be detected between normal individuals. Peripheral blood lymphocytes (PBL) were isolated on three separate occasions from each of 10 healthy volunteers. After exposure of PBL to eight different oxygen tensions ranging from 20% to 0.1%, the expression levels of four HIF-regulated transcripts involved in different biological pathways were measured. The profile of expression of all four transcripts in PBL was related to oxygen tension in a curvilinear manner. Double logarithmic transformation of these data resulted in a linear relationship that allowed the response to be parameterized through a gradient and intercept. Analysis of variance (ANOVA) on these parameters showed that the level of between-subject variation in the gradients of the responses that was common across all four HIF-regulated transcripts was significant ( P = 0.008). We conclude that statistically significant variation within the cellular response to hypoxia can be detected between normal humans. The common nature of the variability across all four HIF-regulated genes suggests that the source of this variation resides within the HIF system itself.

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