scholarly journals Loss of hypoxia-inducible factor 1α affects hypoxia tolerance in larval and adult zebrafish ( Danio rerio )

2020 ◽  
Vol 287 (1927) ◽  
pp. 20200798 ◽  
Author(s):  
Milica Mandic ◽  
Carol Best ◽  
Steve F. Perry
Keyword(s):  
Danio Rerio ◽  
Genome Duplication ◽  
Larval Fish ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Teleost Fishes ◽  
Adult Zebrafish ◽  
Wild Type ◽  
Partial Pressure Of Oxygen ◽  
Hypoxia Inducible Factor 1Α

The coordination of the hypoxic response is attributed, in part, to hypoxia-inducible factor 1α (Hif-1α), a regulator of hypoxia-induced transcription. After the teleost-specific genome duplication, most teleost fishes lost the duplicate copy of Hif-1α, except species in the cyprinid lineage that retained both paralogues of Hif-1α (Hif1aa and Hif1ab). Little is known about the contribution of Hif-1α, and specifically of each paralogue, to hypoxia tolerance. Here, we examined hypoxia tolerance in wild-type (Hif1aa +/+ ab +/+ ) and Hif-1α knockout lines (Hif1aa −/− ; Hif1ab −/− ; Hif1aa −/− ab −/− ) of zebrafish ( Danio rerio ). Critical O 2 tension ( P crit ; the partial pressure of oxygen (PO 2 ) at which O 2 consumption can no longer be maintained) and time to loss of equilibrium (LOE), two indices of hypoxia tolerance, were assessed in larvae and adults. Knockout of both paralogues significantly increased P crit (decreased hypoxia tolerance) in larval fish. Prior exposure of larvae to hypoxia decreased P crit in wild-type fish, an effect mediated by the Hif1aa paralogue. In adults, individuals with a knockout of either paralogue exhibited significantly decreased time to LOE but no difference in P crit . Together, these results demonstrate that in zebrafish, tolerance to hypoxia and improved hypoxia tolerance after pre-exposure to hypoxia (pre-conditioning) are mediated, at least in part, by Hif-1α.

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 Hmox1 (Heme Oxygenase-1) Protects Against Ischemia-Mediated Injury via Stabilization of HIF-1α (Hypoxia-Inducible Factor-1α)

2020 ◽  
Author(s):  
Louise L. Dunn ◽  
Stephanie M.Y. Kong ◽  
Sergey Tumanov ◽  
Weiyu Chen ◽  
James Cantley ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Carbon Monoxide ◽  
Blood Flow ◽  
Heme Oxygenase ◽  
Hypoxia Inducible Factor ◽  
Ischemic Injury ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Tissue Necrosis ◽  
Hypoxia Inducible Factor 1Α

Objective: Hmox1 (heme oxygenase-1) is a stress-induced enzyme that catalyzes the degradation of heme to carbon monoxide, iron, and biliverdin. Induction of Hmox1 and its products protect against cardiovascular disease, including ischemic injury. Hmox1 is also a downstream target of the transcription factor HIF-1α (hypoxia-inducible factor-1α), a key regulator of the body’s response to hypoxia. However, the mechanisms by which Hmox1 confers protection against ischemia-mediated injury remain to be fully understood. Approach and Results: Hmox1 deficient ( Hmox1 –/– ) mice had impaired blood flow recovery with severe tissue necrosis and autoamputation following unilateral hindlimb ischemia. Autoamputation preceded the return of blood flow, and bone marrow transfer from littermate wild-type mice failed to prevent tissue injury and autoamputation. In wild-type mice, ischemia-induced expression of Hmox1 in skeletal muscle occurred before stabilization of HIF-1α. Moreover, HIF-1α stabilization and glucose utilization were impaired in Hmox1 –/– mice compared with wild-type mice. Experiments exposing dermal fibroblasts to hypoxia (1% O 2 ) recapitulated these key findings. Metabolomics analyses indicated a failure of Hmox1 –/– mice to adapt cellular energy reprogramming in response to ischemia. Prolyl-4-hydroxylase inhibition stabilized HIF-1α in Hmox1 –/– fibroblasts and ischemic skeletal muscle, decreased tissue necrosis and autoamputation, and restored cellular metabolism to that of wild-type mice. Mechanistic studies showed that carbon monoxide stabilized HIF-1α in Hmox1 –/– fibroblasts in response to hypoxia. Conclusions: Our findings suggest that Hmox1 acts both downstream and upstream of HIF-1α, and that stabilization of HIF-1α contributes to Hmox1’s protection against ischemic injury independent of neovascularization.

scholarly journals Hypoxia-inducible factor-1 mediates adaptive developmental plasticity of hypoxia tolerance in zebrafish, Danio rerio

2014 ◽  
Vol 281 (1786) ◽  
pp. 20140637 ◽  
Author(s):  
Cayleih E. Robertson ◽  
Patricia A. Wright ◽  
Louise Köblitz ◽  
Nicholas J. Bernier
Keyword(s):  
Danio Rerio ◽  
Cellular Response ◽  
Developmental Plasticity ◽  
Developmental Stages ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Anthropogenic Factors ◽  
Critical Window ◽  
Hypoxia Inducible Factor 1

In recent years, natural and anthropogenic factors have increased aquatic hypoxia the world over. In most organisms, the cellular response to hypoxia is mediated by the master regulator hypoxia-inducible factor-1 (HIF-1). HIF-1 also plays a critical role in the normal development of the cardiovascular system of vertebrates. We tested the hypothesis that hypoxia exposures which resulted in HIF-1 induction during embryogenesis would be associated with enhanced hypoxia tolerance in subsequent developmental stages. We exposed zebrafish ( Danio rerio ) embryos to just 4 h of severe hypoxia or total anoxia at 18, 24 and 36 h post-fertilization (hpf). Of these, exposure to hypoxia at 24 and 36 hpf as well as anoxia at 36 hpf activated the HIF-1 cellular pathway. Zebrafish embryos that acutely upregulated the HIF-1 pathway had an increased hypoxia tolerance as larvae. The critical window for hypoxia sensitivity and HIF-1 signalling was 24 hpf. Adult male fish had a lower critical oxygen tension ( P crit ) compared with females. Early induction of HIF-1 correlated directly with an increased proportion of males in the population. We conclude that mounting a HIF-1 response during embryogenesis is associated with long-term impacts on the phenotype of later stages which could influence both individual hypoxia tolerance and population dynamics.

scholarly journals Sevoflurane Exerts Protective Effects in Murine Peritonitis-induced Sepsis via Hypoxia-inducible Factor 1α/Adenosine A2B Receptor Signaling

2021 ◽  
Author(s):  
Kristian-Christos Ngamsri ◽  
Friederike Fabian ◽  
Anika Fuhr ◽  
Jutta Gamper-Tsigaras ◽  
Andreas Straub ◽  
...  
Keyword(s):  
Intensive Care ◽  
Adhesion Molecules ◽  
Peritoneal Lavage ◽  
Hypoxia Inducible Factor ◽  
Protective Effects ◽  
Wild Type ◽  
Adenosine A2b Receptor ◽  
Hypoxia Inducible Factor 1Α ◽  
A2b Receptor ◽  
Adenosine A2b

Background Sepsis is one of the leading causes of mortality in intensive care units, and sedation in the intensive care unit during sepsis is usually performed intravenously. The inhalative anesthetic sevoflurane has been shown to elicit protective effects in various inflammatory studies, but its role in peritonitis-induced sepsis remains elusive. The hypothesis was that sevoflurane controls the neutrophil infiltration by stabilization of hypoxia-inducible factor 1α and elevated adenosine A2B receptor expression. Methods In mouse models of zymosan- and fecal-induced peritonitis, male mice were anesthetized with sevoflurane (2 volume percent, 30 min) after the onset of inflammation. Control animals received the solvent saline. The neutrophil counts and adhesion molecules on neutrophils in the peritoneal lavage of wild-type, adenosine A2B receptor −/−, and chimeric animals were determined by flow cytometry 4 h after stimulation. Cytokines and protein release were determined in the lavage. Further, the adenosine A2B receptor and its transcription factor hypoxia-inducible factor 1α were evaluated by real-time polymerase chain reaction and Western blot analysis 4 h after stimulation. Results Sevoflurane reduced the neutrophil counts in the peritoneal lavage (mean ± SD, 25 ± 17 × 105vs. 12 ± 7 × 105 neutrophils; P = 0.004; n = 19/17) by lower expression of various adhesion molecules on neutrophils of wild-type animals but not of adenosine A2B receptor −/− animals. The cytokines concentration (means ± SD, tumor necrosis factor α [pg/ml], 523 ± 227 vs. 281 ± 101; P = 0.002; n = 9/9) and protein extravasation (mean ± SD [mg/ml], 1.4 ± 0.3 vs. 0.8 ± 0.4; P = 0.002; n = 12/11) were also lower after sevoflurane only in the wild-type mice. Chimeric mice showed the required expression of the adenosine A2B receptor on the hematopoietic and nonhematopoietic compartments for the protective effects of the anesthetic. Sevoflurane induced the expression of hypoxia-inducible factor 1α and adenosine A2B receptor in the intestine, liver, and lung. Conclusions Sevoflurane exerts various protective effects in two murine peritonitis-induced sepsis models. These protective effects were linked with a functional adenosine A2B receptor. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Hypoxia inducible factor-1 α knockout does not impair acute thermal tolerance or heat hardening in zebrafish

2020 ◽  
Vol 16 (7) ◽  
pp. 20200292
Author(s):  
William Joyce ◽  
Steve F. Perry
Keyword(s):  
High Temperature ◽  
Thermal Tolerance ◽  
Hypoxia Inducible Factor ◽  
Extreme Environments ◽  
Hypoxia Tolerance ◽  
Similar Degree ◽  
Wild Type ◽  
Double Knockout ◽  
Hypoxia Inducible Factor 1 ◽  
Heat Hardening

The rapid increase in critical thermal maximum (CT max ) in fish (or other animals) previously exposed to critically high temperature is termed ‘heat hardening’, which likely represents a key strategy to cope with increasingly extreme environments. The physiological mechanisms that determine acute thermal tolerance, and the underlying pathways facilitating heat hardening, remain debated. It has been posited, however, that exposure to high temperature is associated with tissue hypoxia and may be associated with the increased expression of hypoxia-inducible factor-1 (Hif-1). We studied acute thermal tolerance in zebrafish ( Danio rerio ) lacking functional Hif-1 α paralogs (Hif-1aa and Hif-1ab double knockout; Hif-1 α −/− ), which are known to exhibit markedly reduced hypoxia tolerance. We hypothesized that Hif-1 α −/− zebrafish would suffer reduced acute thermal tolerance relative to wild type and that the heat hardening ability would be lost. However, on the contrary, we observed that Hif-1 α −/− and wild-type fish did not differ in CT max , and both genotypes exhibited heat hardening of a similar degree when CT max was re-tested 48 h later. Despite exhibiting impaired hypoxia tolerance, Hif-1 α −/− zebrafish display unaltered thermal tolerance, suggesting that these traits are not necessarily functionally associated. Hif-1 α is accordingly not required for short-term acclimation in the form of heat hardening.

scholarly journals Specific cyprinid HIF isoforms contribute to cellular mitochondrial regulation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jing Chen ◽  
Lihong Guan ◽  
Ming Zou ◽  
Shunping He ◽  
Dapeng Li ◽  
...  
Keyword(s):  
Cellular Response ◽  
Genome Duplication ◽  
Citrate Synthase ◽  
Tricarboxylic Acid Cycle ◽  
Hypoxia Inducible Factor ◽  
Cyprinid Fish ◽  
Hypoxia Tolerance ◽  
Mitochondrial Mass ◽  
Mitochondrial Regulation ◽  
Hypoxia Inducible Factor 1

Abstract Hypoxia-inducible factor 1 (HIF-1) functions as a master regulator of the cellular response to hypoxic stress. Two HIF-1α paralogs, HIF-1αA and HIF-1αB, were generated in euteleosts by the specific, third round of genome duplication, but one paralog was later lost in most families with the exception of cyprinid fish. How these duplicates function in mitochondrial regulation and whether their preservation contributes to the hypoxia tolerance demonstrated by cyprinid fish in freshwater environments is not clear. Here we demonstrated the divergent function of these two zebrafish Hif-1a paralogs through cellular approaches. The results showed that Hif-1aa played a role in tricarboxylic acid cycle by increasing the expression of Citrate synthase and the activity of mitochondrial complex II, and it also enhanced mitochondrial membrane potential and ROS production by reducing free Ca2+ in the cytosol. Hif-1ab promoted intracellular ATP content by up-regulating the activity of mitochondrial complexes I, III and IV and the expression of related genes. Furthermore, both the two zebrafish Hif-1a paralogs promoted mitochondrial mass and the expression level of mtDNA, contributing to mitochondrial biogenesis. Our study reveals the divergent functions of Hif-1aa and Hif-1ab in cellular mitochondrial regulation.

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