Update on hypoxia-inducible factors and hydroxylases in oxygen regulatory pathways: from physiology to therapeutics

Ratcliffe, Peter J.; Koivunen, Peppi; Myllyharju, Johanna; Ragoussis, Jiannis; Bovée, Judith V.M.G.; Batinić‐Haberle, Ines; Vinatier, Claire; Trichet, Valérie; Robriquet, Florence; Oliver, Lisa; Gardie, Betty

doi:10.2147/hp.s127042

Cited by 29 publications

(21 citation statements)

References 75 publications

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“…96 Hypoxia-induced factor-1 alpha (HIF1A) is a master transcriptional regulator of cellular response to hypoxia. 98,99 Thus, we hypothesized that apical hypoxia in GuMI culture would induce hypoxia-related responses in colon epithelia and promote epithelial barrier functions. First, we found under hypoxic conditions HIF1A gene expression was significantly increased (p = 0.0001) in GuMI-NB compared with Static cells cultured in normoxia, with a fold change of 1.52 (Figure 4a and 4b).…”

Section: Gumi Recapitulates Cell Responses To Hypoxiamentioning

confidence: 99%

Primary human colonic mucosal barrier crosstalk with super oxygen-sensitiveFaecalibacterium prausnitziiin continuous culture

Zhang

Huang

Yoon

et al. 2020

Preprint

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AbstractThe gut microbiome plays an important role in human health and disease. Gnotobiotic animal and in vitro cell-based models provide some informative insights into mechanistic crosstalk. However, there is no existing system for a chronic co-culture of a human colonic mucosal barrier with super oxygen-sensitive commensal microbes, hindering the study of human-microbe interactions in a controlled manner. Here, we investigated the effects of an abundant super oxygen-sensitive commensal anaerobe, Faecalibacterium prausnitzii, on a primary human mucosal barrier using a Gut-MIcrobiome (GuMI) physiome platform that we designed and fabricated. Chronic continuous co-culture of F. prausnitzii for two days with colon epithelia, enabled by continuous flow of completely anoxic apical media and aerobic basal media, resulted in a strictly anaerobic apical environment fostering growth of and butyrate production by F. prausnitzii, while maintaining a stable colon epithelial barrier. We identified elevated differentiation and hypoxia-responsive genes and pathways in the platform compared with conventional aerobic static culture of the colon epithelia, attributable to a combination of anaerobic environment and continuous medium replenishment. Furthermore, we demonstrated anti-inflammatory effects of F. prausnitzii through HDAC and the TLR-NFKB axis. Finally, we identified that butyrate largely contributes to the anti-inflammatory effects by downregulating TLR3 and TLR4. Our results are consistent with some clinical observations regarding F. prausnitzii, thus motivating further studies employing this platform with more complex engineered colon tissues for understanding the interaction between the human colonic mucosal barrier and microbiota, pathogens, or engineered bacteria.

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Section: Gumi Recapitulates Cell Responses To Hypoxiamentioning

confidence: 99%

Primary human colonic mucosal barrier crosstalk with super oxygen-sensitiveFaecalibacterium prausnitziiin continuous culture

Zhang

Huang

Yoon

et al. 2020

Preprint

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“…Such toxicityi sd ue to its micellar properties, involving the presence of hydrophobic alkyl chains and cationic nitrogens that are polar.O ne way to eliminate such toxicityi nvolves replacing CH 2 groups by oxygen atoms that are buried deep in the long heptylc hains. [116] The study by Ali et al demonstrated that the Mn 3 + mesotetrakis (N-methylpyridinium-2-yl) porphyrin (MnTM-2-PyP) reduced diabetes-induced oxidative stress and extended the lifespan of STZ diabetic rats if administered during the onset of diabetes. The presence of these oxygens,t ogether with the high lipophilicity confer excellent chemical and physical properties to Mn 3 + meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP 5 + (MnBuOE, BMX-001).…”

Section: Manganese Porphyrinsmentioning

confidence: 99%

Potential Therapeutic Applications of MnSODs and SOD‐Mimetics

Bonetta

2017

Chemistry A European J

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Natural as well as synthetic antioxidants are constantly being investigated for their efficiency in combatting the effects of oxidative stress, which appears to be the responsible cause of several diseases, including cancer, central nervous system disorders, ischaemia-reperfusion disorders, cardiovascular conditions, and diabetes. Superoxide dismutases (SODs) constitute the ubiquitous antioxidant defences against oxidative stress that underlies numerous pathological conditions. Therefore, the development of therapeutics aimed at either delivering MnSOD more effectively to target tissues in the body in the form of MnSOD gene therapy, or the synthesis of molecules that mimic the activity of superoxide dismutase is constantly being explored. Classes that have been developed as SOD mimetics include the Mn-metalloporphyrins, Mn-cyclic polyamines, Mn-salen complexes, MnPLED derivatives as well as the nitroxides. Thus far, SOD mimetics have shown remarkable efficacy in several animal models suffering from oxidative stress injuries. A promising approach for the future of SOD and SOD mimic therapeutics appears to involve combination treatment of the antioxidants with radiotherapy or chemotherapy.

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“…; Ratcliffe et al . ). In recent work, we have observed that general inactivation of HIF‐2α, but not HIF‐1α, ablates the proliferation that occurs within days of exposure to hypoxia in adult mice (Hodson et al .…”

Section: Introductionmentioning

confidence: 97%

PHD2 inactivation in Type I cells drives HIF‐2α‐dependent multilineage hyperplasia and the formation of paraganglioma‐like carotid bodies

Fielding

Hodson

Cheng

et al. 2018

The Journal of Physiology

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Key points The carotid body is a peripheral arterial chemoreceptor that regulates ventilation in response to both acute and sustained hypoxia.Type I cells in this organ respond to low oxygen both acutely by depolarization and dense core vesicle secretion and, over the longer term, via cellular proliferation and enhanced ventilatory responses.Using lineage analysis, the present study shows that the Type I cell lineage itself proliferates and expands in response to sustained hypoxia.Inactivation of HIF‐2α in Type I cells impairs the ventilatory, proliferative and cell intrinsic (dense core vesicle) responses to hypoxia.Inactivation of PHD2 in Type I cells induces multilineage hyperplasia and ultrastructural changes in dense core vesicles to form paraganglioma‐like carotid bodies.These changes, similar to those observed in hypoxia, are dependent on HIF‐2α.Taken together, these findings demonstrate a key role for the PHD2–HIF‐2α couple in Type I cells with respect to the oxygen sensing functions of the carotid body. AbstractThe carotid body is a peripheral chemoreceptor that plays a central role in mammalian oxygen homeostasis. In response to sustained hypoxia, it manifests a rapid cellular proliferation and an associated increase in responsiveness to hypoxia. Understanding the cellular and molecular mechanisms underlying these processes is of interest both to specialized chemoreceptive functions of that organ and, potentially, to the general physiology and pathophysiology of cellular hypoxia. We have combined cell lineage tracing technology and conditionally inactivated alleles in recombinant mice to examine the role of components of the HIF hydroxylase pathway in specific cell types within the carotid body. We show that exposure to sustained hypoxia (10% oxygen) drives rapid expansion of the Type I, tyrosine hydroxylase expressing cell lineage, with little transdifferentiation to (or from) that lineage. Inactivation of a specific HIF isoform, HIF‐2α, in the Type I cells was associated with a greatly reduced proliferation of Type I cells and hypoxic ventilatory responses, with ultrastructural evidence of an abnormality in the action of hypoxia on dense core secretory vesicles. We also show that inactivation of the principal HIF prolyl hydroxylase PHD2 within the Type I cell lineage is sufficient to cause multilineage expansion of the carotid body, with characteristics resembling paragangliomas. These morphological changes were dependent on the integrity of HIF‐2α. These findings implicate specific components of the HIF hydroxylase pathway (PHD2 and HIF‐2α) within Type I cells of the carotid body with respect to the oxygen sensing and adaptive functions of that organ.

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Update on hypoxia-inducible factors and hydroxylases in oxygen regulatory pathways: from physiology to therapeutics

Cited by 29 publications

References 75 publications

Primary human colonic mucosal barrier crosstalk with super oxygen-sensitiveFaecalibacterium prausnitziiin continuous culture

Primary human colonic mucosal barrier crosstalk with super oxygen-sensitiveFaecalibacterium prausnitziiin continuous culture

Potential Therapeutic Applications of MnSODs and SOD‐Mimetics

PHD2 inactivation in Type I cells drives HIF‐2α‐dependent multilineage hyperplasia and the formation of paraganglioma‐like carotid bodies

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