The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases

Acker, Till; Fandrey, Joachim; Acker, H.

doi:10.1016/j.cardiores.2006.04.008

Cited by 104 publications

(85 citation statements)

References 110 publications

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“…This leads to DNA damage, depletion of intracellular antioxidant defense system, alteration in calcium homeostasis and apoptosis [30] and further causes pathophysiology. On the contrary, the oxidant-antioxidant homeostasis, leading to low levels of ROS production may serve as messengers in order to activate signaling pathways and is also involved in O 2 sensing that influences HIF stability [31]. Our results demonstrated that conditioning the rats to 10 days of IH leads to highly significant rise in the SOD2 when compared to control, which is a unique finding of this study.…”

Section: Discussionsupporting

confidence: 51%

Alterations in Carotid Body Morphology and Cellular Mechanism Under the Influence of Intermittent Hypoxia

2017

IJCRR

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Aims: Intermittent hypoxia (IH) training is said to have a preconditioning effect for evoking acclimatization at high altitude (HA). Carotid body (CB) plays a vital role in oxygen sensing and is an important component in HA acclimatization. The present study reports the mechanistic effects of IH that involves episodes of hypoxia of few hours continued for several days, on the CB responses to acute hypobaric hypoxia in terms of morphological changes in CB and its cellular functions.Methodology: 24 Sprague-Dawley (250-300g) rats were divided into 2 major groups: 1) control, 2) experimental group (n=12 each) in which the rats were exposed to IH training for 10 days with a single hypoxic episode of 4h/day at a simulated altitude of 15000ft. 6 rats from each group were further subjected to a simulated hypobaric acute hypoxic (AH) challenge of 1hr at 25000ft to see the effect of IH training (IHT) and were named as 3) Control+ AH challenge and 4) IHT+ AH challenge. Morphological changes in CB in different groups were observed along with expression of hypoxia inducible factor (HIF) 1α, HIF2α, NADPH Oxidase 2 (NOX2) and Superoxide Dismutase 2 (SOD2) using immunohistochemistry for the first time. Results:The results showed that IH training leads to morphological changes in terms of hyperplasia and unaltered HIF1α levels along with a highly significant rise in HIF2α in CB. When the rats are exposed to AH without IH conditioning, there is a significant rise in HIF1α and thus NOX2 levels. However, prior exposure to IH leads to a significant rise in the HIF2α levels and thus SOD2 levels, when subjected to AH challenge. Discussion and Conclusion:These results indicate that IH training affects the cellular response of CB by regulating balanced expression of both HIF1α and HIF2α, thus modulating the cellular redox state by promoting the antioxidant enzyme production and suppressing the pro-oxidant enzyme levels, thereby playing a crucial role in pre-conditioning to acute hypoxia.

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Section: Discussionsupporting

confidence: 51%

Alterations in Carotid Body Morphology and Cellular Mechanism Under the Influence of Intermittent Hypoxia

2017

IJCRR

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“…The hypoxia inducible transcription factor 1 (HIF-1) activates an array of more than 70 target genes that support hypoxic survival and anaerobic energy production under physiological conditions, which cause severe downfall of the intracellular oxygen tension (Acker et al 2006). HIF dependent hypoxic regulation has so far been identified in mammals, fish, invertebrates, and yeast, and a multitude of review papers summarize the complex state of present knowledge on its physiological role and regulation in different model and non-model systems (Huang and Bunn 2003;Acker and Acker 2004;Gorr et al 2006;Fandrey et al 2006;Acker et al 2006).…”

Section: Introductionmentioning

confidence: 99%

“…HIF dependent hypoxic regulation has so far been identified in mammals, fish, invertebrates, and yeast, and a multitude of review papers summarize the complex state of present knowledge on its physiological role and regulation in different model and non-model systems (Huang and Bunn 2003;Acker and Acker 2004;Gorr et al 2006;Fandrey et al 2006;Acker et al 2006). The molecular mechanisms involved in HIF regulation have been most thoroughly investigated in mammalian tissues and cell models.…”

Section: Introductionmentioning

confidence: 99%

“…As several steps of the oxygen sensitive signalling cascade (stabilisation of HIF-1a, DNA binding activity of HIF-1) are redox controlled (Haddad et al 2000;Nikinmaa et al 2004) and modulated by reactive oxygen species (ROS) formation (Acker et al 2006), we suspected that oxidative stress, but also the content of unbound free iron in the tissues could affect the HIF response (Czubryt et al 1996;Nikinmaa 2002). Therefore a variety of cellular oxidative stress parameters (oxidative damage and antioxidant defence), the cellular redox state (GSSG:GSH) and also the levels of bound and labile iron were tested in liver tissues of both fish at warm and cold temperatures.…”

Section: Introductionmentioning

confidence: 99%

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Effects of seasonal and latitudinal cold on oxidative stress parameters and activation of hypoxia inducible factor (HIF-1) in zoarcid fish

Heise

Estevez²,

Puntarulo³

et al. 2007

J Comp Physiol B

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Acute, short term cooling of North Sea eelpout Zoarces viviparus is associated with a reduction of tissue redox state and activation of hypoxia inducible factor (HIF-1) in the liver. The present study explores the response of HIF-1 to seasonal cold in Zoarces viviparus, and to latitudinal cold by comparing the eurythermal North Sea fish to stenothermal Antarctic eelpout (Pachycara brachycephalum). Hypoxic signalling (HIF-1 DNA binding activity) was studied in liver of summer and winter North Sea eelpout as well as of Antarctic eelpout at habitat temperature of 0°C and after long-term warming to 5°C. Biochemical parameters like tissue iron content, glutathione redox ratio, and oxidative stress indicators were analyzed to see whether the cellular redox state or reactive oxygen species formation and HIF activation in the fish correlate. HIF-1 DNA binding activity was significantly higher at cold temperature, both in the interspecific comparison, polar vs. temperate species, and when comparing winter and summer North Sea eelpout. Compared at the low acclimation temperatures (0°C for the polar and 6°C for the temperate eelpout) the polar fish showed lower levels of lipid peroxidation although the liver microsomal fraction turned out to be more susceptible to lipid radical formation. The level of radical scavenger, glutathione, was twofold higher in polar than in North Sea eelpout and also oxidised to over 50%. Under both conditions of cold exposure, latitudinal cold in the Antarctic and seasonal cold in the North Sea eelpout, the glutathione redox ratio was more oxidised when compared to the warmer condition. However, oxidative damage parameters (protein carbonyls and thiobarbituric acid reactive substances (TBARS) were elevated only during seasonal cold exposure in Z. viviparus. Obviously, Antarctic eelpout are keeping oxidative defence mechanisms high enough to avoid accumulation of oxidative damage products at low habitat temperature. The paper discusses how HIF could be instrumental in cold adaptation in fish.

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“…Under normoxia, HIF-α subunit is degraded following hydroxylation at proline residues by prolylhydroxylases (PHD), which allows the binding of the E3 ubiquitin ligase pVHL for proteasome-targeted degradation [9][10][11]. Under normoxia, HIF-α is also hydroxylated at asparagine residues by the asparaginyl-hydroxylase Factor Inhibiting HIF-1 (FIH) to prevent interactions with co-activators such as p300 and aberrant transcriptional activation [10,11]. In contrast, the β-subunit is not regulated by oxygen levels and is constitutively expressed in the nucleus.…”

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confidence: 99%

Hypoxic Stress: A Key Regulator of the Antitumor Cytotoxic Response Linking Immune Resistance to Immune Suppression

Hasmim

Messai²,

Terry³

et al. 2014

J Mol Genet Med

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EditorialThe tumor microenvironment is a complex network of tumor cells, immune cells, stromal cells and extracellular matrix accomplishing proliferation, migration, and dissemination of tumor cells. The reactivity of the immune system towards the growing tumor determines its capacity to reject the tumor, but this reactivity is increasingly appearing to be critically dependent on tumor microenvironmental factors. These factors include secreted molecules, type of infiltrating cells, and metabolic component such as hypoxia. Microenvironmental hypoxia is a prominent feature of solid tumors and is involved in fostering the neoplastic process and in modulation of immune reactivity. It results from inadequacies between the tumor microcirculation and the oxygen demands of the growing tumor mass, which leads to a lowering of oxygen partial pressure and a metabolic switch towards glycolysis [1]. Tumor hypoxia is a negative prognostic and predictive factor due to many effects on the selection of hypoxiasurviving clones [2], activation of the expression of genes involved in apoptosis inhibition [3], angiogenesis [4], invasiveness and metastasis [5], epithelial-to-mesenchymal transition [6], and loss of genomic stability [7]. Accumulating evidence indicates that tumor hypoxia is also involved in loss of immune reactivity either by decreasing tumor cell sensitivity to cytotoxic effectors or promoting immunosuppressive mechanisms [8].The major effects of hypoxia are mediated through the stabilization of Hypoxia-inducible factors (HIFs) composed of a basic helix-loophelix/PAS protein (HIF-α) and the aryl hydrocarbon nuclear translocator (ARNT or HIF-β). Under normoxia, HIF-α subunit is degraded following hydroxylation at proline residues by prolylhydroxylases (PHD), which allows the binding of the E3 ubiquitin ligase pVHL for proteasome-targeted degradation [9][10][11]. Under normoxia, HIF-α is also hydroxylated at asparagine residues by the asparaginyl-hydroxylase Factor Inhibiting HIF-1 (FIH) to prevent interactions with co-activators such as p300 and aberrant transcriptional activation [10,11]. In contrast, the β-subunit is not regulated by oxygen levels and is constitutively expressed in the nucleus. Hypoxia inhibits the hydroxylation of proline and asparagine residues, allowing HIF-α nuclear translocation and binding to HIF-β for full transcriptional activation.Recently, we provided evidence indicating that hypoxia induced resistance of tumor cells to the lytic action of cytotoxic effector cells via several HIF-1α -dependent mechanisms involving activation of Stat3 [12] More interestingly, the expression of T cell inhibitory checkpoints was found to be regulated by hypoxic stress. We have recently shown that hypoxia induced up-regulation of Program Death-Ligand 1 (PD-L1), ligand of the inhibitory checkpoint PD-, on both tumor and Myeloid-Derived Suppressor Cells (MDSC) via direct binding of HIF-1 to PD-L1 promoter [19]. This establishes a direct link between immunosuppressive mechanisms and hypoxic signalling. Based on th...

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The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases

Cited by 104 publications

References 110 publications

Alterations in Carotid Body Morphology and Cellular Mechanism Under the Influence of Intermittent Hypoxia

Alterations in Carotid Body Morphology and Cellular Mechanism Under the Influence of Intermittent Hypoxia

Effects of seasonal and latitudinal cold on oxidative stress parameters and activation of hypoxia inducible factor (HIF-1) in zoarcid fish

Hypoxic Stress: A Key Regulator of the Antitumor Cytotoxic Response Linking Immune Resistance to Immune Suppression

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