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.

Hypoxia-inducible carbonic anhydrase IX expression is insufficient to alleviate intracellular metabolic acidosis in the muscle of zebrafish,Danio rerio

2009 ◽  
Vol 296 (1) ◽  
pp. R150-R160 ◽  
Author(s):  
Andrew J. Esbaugh ◽  
S. F. Perry ◽  
K. M. Gilmour
Keyword(s):  
Carbonic Anhydrase ◽  
Physiological Function ◽  
Hypoxia Inducible Factor ◽  
Regulatory Control ◽  
Hypoxic Exposure ◽  
Intracellular Acidosis ◽  
Ca Ix ◽  
Muscle Ph ◽  
Exercise Induced ◽  
The Impact

Recent evidence suggests that carbonic anhydrase (CA) IX in humans is under the regulatory control of hypoxia-inducible factor and is overexpressed in certain cancers. However, little is known of its presence in nonmammalian vertebrates or its physiological function in any vertebrate. The objective of this study was to examine and characterize the presence, distribution, induction by hypoxia, and physiological function of CA IX in the zebrafish. Zebrafish CA IX was highly expressed in the eye, brain, and gastrointestinal tract and showed increased expression in the eye, brain, and muscle in response to hypoxia (water Po2= 24 mmHg). The hypothesis that increased CA IX expression during hypoxia would act to attenuate intracellular acidosis was then examined. Muscle intracellular pH (pHi) decreased after 4 h of hypoxic exposure (from 7.15 ± 0.02 to 7.06 ± 0.01 pH units) and did not recover by 24 h. Manipulation of extracellular CA activity via intraperitoneal injection of either bovine CA or the selective extracellular CA inhibitor F3500 revealed that although increased CA activity could fully restore pHi, removal of extracellular activity did not result in further acidosis. An exercise-induced acidosis was also attenuated in fish treated with bovine CA; however, the increased extracellular CA expression resulting from hypoxia had no affect. These data suggest that although extracellular CA can potentially minimize the impact of hypoxia on muscle pHi, the actual level of extracellular CA activity is likely insufficient to achieve this goal, even when enhanced by hypoxia-induced increases in CA IX expression.

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

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 428
Author(s):  
Dzhuliia Dzhalilova ◽  
Olga Makarova
Keyword(s):  
Oxygen Deficiency ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Alternative Methods ◽  
Detection Methods ◽  
Hypoxic Exposure ◽  
Tumor Diseases ◽  
Direct Exposure ◽  
The Moment ◽  
Potential Biomarkers

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.

scholarly journals Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

2015 ◽  
Vol 212 (13) ◽  
pp. 2223-2234 ◽  
Author(s):  
Milica Vukovic ◽  
Amelie V. Guitart ◽  
Catarina Sepulveda ◽  
Arnaud Villacreces ◽  
Eoghan O'Duibhir ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Hypoxia Inducible Factor ◽  
Leukemic Cells ◽  
Wild Type ◽  
Hypoxic Conditions ◽  
Downstream Effectors ◽  
Human Acute Myeloid Leukemia ◽  
Genetic Deletion ◽  
Hif Pathway ◽  
The Impact

Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance.

scholarly journals GRK6 Depletion Induces HIF Activity in Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Sumei Yao ◽  
Ayse Ertay ◽  
Yilu Zhou ◽  
Liudi Yao ◽  
Charlotte Hill ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Hypoxia Inducible Factor ◽  
Lung Epithelial Cells ◽  
Alveolar Epithelial ◽  
Hypoxia Inducible Factor 1 ◽  
Lung Epithelial ◽  
Hif Pathway ◽  
The Impact ◽  
G Protein Coupled

G protein-coupled receptor kinase 6 (GRK6) is expressed in various tissues and is involved in the development of several diseases including lung cancer. We previously reported that GRK6 is down-regulated in lung adenocarcinoma patients, which induces cell invasion and metastasis. However, further understanding of the role of GRK6 in lung adenocarcinoma is required. Here we explored the functional consequence of GRK6 inhibition in lung epithelial cells. Analysis of TCGA data was coupled with RNA sequencing (RNA-seq) in alveolar epithelial type II (ATII) cells following depletion of GRK6 with RNA interference (RNAi). Findings were validated in ATII cells followed by tissue microarray analysis. Pathway analysis suggested that one of the Hallmark pathways enriched upon GRK6 inhibition is ‘Hallmark_Hypoxia’ (FDR = 0.014). We demonstrated that GRK6 depletion induces HIF1α (hypoxia-inducible factor 1 alpha) levels and activity in ATII cells. The findings were further confirmed in lung adenocarcinoma samples, in which GRK6 expression levels negatively and positively correlate with HIF1α expression (P = 0.015) and VHL expression (P < 0.0001), respectively. Mechanistically, we showed the impact of GRK6 on HIF activity could be achieved via regulation of VHL levels. Taken together, targeting the HIF pathway may provide new strategies for therapy in GRK6-depleted lung adenocarcinoma patients.

scholarly journals Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2340
Author(s):  
Mykyta I. Malkov ◽  
Chee Teik Lee ◽  
Cormac T. Taylor
Keyword(s):  
Inflammatory Cytokines ◽  
Cellular Response ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Wide Range ◽  
Inflammatory Stimuli ◽  
Factor Α ◽  
Hif Pathway ◽  
The Impact ◽  
Pro Inflammatory Cytokines

Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.

scholarly journals Hypoxia Pathway Proteins in Normal and Malignant Hematopoiesis

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 155 ◽  
Author(s):  
Ben Wielockx ◽  
Tatyana Grinenko ◽  
Peter Mirtschink ◽  
Triantafyllos Chavakis
Keyword(s):  
Cell Fate ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Adult Life ◽  
Low Oxygen ◽  
Hematopoietic Stem ◽  
Metabolism Regulation ◽  
Hsc Niche ◽  
Hif Pathway ◽  
The Impact

The regulation of oxygen (O2) levels is crucial in embryogenesis and adult life, as O2 controls a multitude of key cellular functions. Low oxygen levels (hypoxia) are relevant for tissue physiology as they are integral to adequate metabolism regulation and cell fate. Hence, the hypoxia response is of utmost importance for cell, organ and organism function and is dependent on the hypoxia-inducible factor (HIF) pathway. HIF pathway activity is strictly regulated by the family of oxygen-sensitive HIF prolyl hydroxylase domain (PHD) proteins. Physiologic hypoxia is a hallmark of the hematopoietic stem cell (HSC) niche in the bone marrow. This niche facilitates HSC quiescence and survival. The present review focuses on current knowledge and the many open questions regarding the impact of PHDs/HIFs and other proteins of the hypoxia pathway on the HSC niche and on normal and malignant hematopoiesis.

Oxygen-dependent gene expression in fishes

2005 ◽  
Vol 288 (5) ◽  
pp. R1079-R1090 ◽  
Author(s):  
Mikko Nikinmaa ◽  
Bernard B. Rees
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Hypoxia Tolerance ◽  
Hypoxic Exposure ◽  
Low Oxygen ◽  
Mammalian Development ◽  
Molecular Responses ◽  
And Function

The role of oxygen in regulating patterns of gene expression in mammalian development, physiology, and pathology has received increasing attention, especially after the discovery of the hypoxia-inducible factor (HIF), a transcription factor that has been likened to a “master switch” in the transcriptional response of mammalian cells and tissues to low oxygen. At present, considerably less is known about the molecular responses of nonmammalian vertebrates and invertebrates to hypoxic exposure. Because many animals live in aquatic habitats that are variable in oxygen tension, it is relevant to study oxygen-dependent gene expression in these animals. The purpose of this review is to discuss hypoxia-induced gene expression in fishes from an evolutionary and ecological context. Recent studies have described homologs of HIF in fish and have begun to evaluate their function. A number of physiological processes are known to be altered by hypoxic exposure of fish, although the evidence linking them to HIF is less well developed. The diversity of fish presents many opportunities to evaluate if inter- and intraspecific variation in HIF structure and function correlate with hypoxia tolerance. Furthermore, as an aquatic group, fish offer the opportunity to examine the interactions between hypoxia and other stressors, including pollutants, common in aquatic environments. It is possible, if not likely, that results obtained by studying the molecular responses of fish to hypoxia will find parallels in the oxygen-dependent responses of mammals, including humans. Moreover, novel responses to hypoxia could be discovered through studies of this diverse and species-rich group.

scholarly journals Aquatic surface respiration improves survival during hypoxia in zebrafish ( Danio rerio ) lacking hypoxia-inducible factor 1-α

2022 ◽  
Vol 289 (1966) ◽  
Author(s):  
Milica Mandic ◽  
Kaitlyn Flear ◽  
Pearl Qiu ◽  
Yihang K. Pan ◽  
Steve F. Perry ◽  
...  
Keyword(s):  
Danio Rerio ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Wild Type ◽  
Survival Times ◽  
Aquatic Surface Respiration ◽  
Negative Effects ◽  
Hypoxia Inducible Factor 1 ◽  
Impact On Survival ◽  
The Impact

Hypoxia-inducible factor 1-α (Hif-1α), an important transcription factor regulating cellular responses to reductions in O 2 , previously was shown to improve hypoxia tolerance in zebrafish ( Danio rerio ). Here, we examined the contribution of Hif-1α to hypoxic survival, focusing on the benefit of aquatic surface respiration (ASR). Wild-type and Hif-1α knockout lines of adult zebrafish were exposed to two levels (moderate or severe) of intermittent hypoxia. Survival was significantly compromised in Hif-1α knockout zebrafish prevented from accessing the surface during severe (16 mmHg) but not moderate (23 mmHg) hypoxia. When allowed access to the surface in severe hypoxia, survival times did not differ between wild-type and Hif-1α knockouts. Performing ASR mitigated the negative effects of the loss of Hif-1α with the knockouts initiating ASR at a higher P O 2 threshold and performing ASR for longer than wild-types. The loss of Hif-1α had little impact on survival in fish between 1 and 5 days post-fertilization, but as the larvae aged, their reliance on Hif-1α increased. Similar to adult fish, ASR compensated for the loss of Hif-1α on survival. Together, these results demonstrate that age, hypoxia severity and, in particular, the ability to perform ASR significantly modulate the impact of Hif-1α on survival in hypoxic zebrafish.

scholarly journals Impact of the Whole Genome Duplication Event on PYK Activity and Effects of a PYK1 Mutation on Metabolism in S. cerevisiae

2021 ◽  
Vol 8 ◽  
Author(s):  
Hong Chen ◽  
Jamie E. Blum ◽  
Anna Thalacker-Mercer ◽  
Zhenglong Gu
Keyword(s):  
Ethanol Production ◽  
Whole Genome Duplication ◽  
Genome Duplication ◽  
Cell Metabolism ◽  
Glucose Consumption ◽  
Duplication Event ◽  
Whole Genome ◽  
Genome Duplication Event ◽  
Yeast Metabolism ◽  
The Impact

Background: Evolution of aerobic fermentation (crabtree effect) in yeast is associated with the whole genome duplication (WGD) event, suggesting that duplication of certain genes may have altered yeast metabolism. The pyruvate kinase (PYK) gene is associated with alterations in cell metabolism, and duplicated during the WGD, generating PYK1 and PYK2. Thus, the impact of WGD on PYK activity and role of PYK in yeast metabolism were explored.Methods: PYK activity in the presence or absence of fructose-1,6-bisphosphate (FBP) was compared between pre- and post-WGD yeast. Glucose consumption, ethanol production, and oxygen consumption were measured in wildtype yeast and yeast with a T403E point mutation, which alters FBP binding affinity.Results: FBP stimulated increased PYK activity in pre-WGD yeast and in the PYK1 isoforms of post-WGD yeast, but not in the PYK2 isoforms of post-WGD yeast. Compared to wildtype, T403E mutant yeast displayed reduced glucose consumption, reduced ethanol production, and increased mitochondrial metabolism.Conclusion: The WGD event impacted the sensitivity of PYK activity to FBP. Mutations in the FBP binding domain of PYK induce metabolic shifts that favor respiration and suppress fermentation.

scholarly journals Severe hypoxia exposure inhibits larval brain development but does not affect the capacity to mount a cortisol stress response in zebrafish

2021 ◽  
Author(s):  
Kristina V. Mikloska ◽  
Zoe A. Zrini ◽  
Nicholas J. Bernier
Keyword(s):  
Stress Response ◽  
Brain Development ◽  
Hypoxia Tolerance ◽  
Severe Hypoxia ◽  
Whole Body ◽  
Hypoxic Exposure ◽  
Larval Brain ◽  
Fish Nursery ◽  
Hypoxia Exposure ◽  
The Impact

Fish nursery habitats are increasingly hypoxic and the brain is recognized as highly hypoxia-sensitive, yet there is a lack of information on the effects of hypoxia on the development and function of the larval fish brain. Here, we tested the hypothesis that by inhibiting brain development, larval exposure to severe hypoxia has persistent functional effects on the cortisol stress response in zebrafish (Danio rerio). Exposing 5 days post-fertilization (dpf) larvae to 10% dissolved O2 (DO) for 16 h only marginally reduced survival, but it decreased forebrain neural proliferation by 55%, and reduced the expression of neurod1, gfap, and mbpa, markers of determined neurons, glia, and oligodendrocytes, respectively. The 5 dpf hypoxic exposure also elicited transient increases in whole body cortisol and in crf, uts1, and hsd20b2 expression, key regulators of the endocrine stress response. Hypoxia exposure at 5 dpf also inhibited the cortisol stress response to hypoxia in 10 dpf larvae and increased hypoxia tolerance. However, 10% DO exposure at 5 dpf for 16h did not affect the cortisol stress response to a novel stressor in 10 dpf larvae or the cortisol stress response to hypoxia in adult fish. Therefore, while larval exposure to severe hypoxia can inhibit brain development, it also increases hypoxia tolerance. These effects may transiently reduce the impact of hypoxia on the cortisol stress response but not its functional capacity to respond to novel stressors. We conclude that the larval cortisol stress response in zebrafish has a high capacity to cope with severe hypoxia-induced neurogenic impairment.

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