The Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis

UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Gastroenterology (Impact Factor: 16.72). 01/2008; 134(1):156-65. DOI: 10.1053/j.gastro.2007.10.012
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Prolyl and asparaginyl hydroxylases are key oxygen-sensing enzymes that confer hypoxic sensitivity to transcriptional regulatory pathways including the hypoxia inducible factor 1 (HIF-1) and nuclear factor-kappaB (NF-kappaB). Knockout of either HIF-1 or (IKKbeta-dependent) NF-kappaB pathways in intestinal epithelial cells promotes inflammatory disease in murine models of colitis. Both HIF-1 and NF-kappaB pathways are repressed by the action of hydroxylases through the hydroxylation of key regulatory molecules.
In this study we have investigated the effects of the hydroxylase inhibitor dimethyloxalylglycine (DMOG) on Caco-2 intestinal epithelial cells in vitro and in a dextran sodium sulfate-induced model of murine colitis.
DMOG induces both HIF-1 and NF-kappaB activity in cultured intestinal epithelial cells, and is profoundly protective in dextran-sodium sulfate colitis in a manner that is at least in part reflected by the development of an anti-apoptotic phenotype in intestinal epithelial cells, which we propose reduces epithelial barrier dysfunction.
These data show that hydroxylase inhibitors such as DMOG represent a new strategy for the treatment of inflammatory bowel disease.

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    • "In this regard, DMOG can contribute to improved cell survival and tissue restoration reported in vivo in the DSS-induced colitis model (Fig. 8E) [20]. Particularly relevant is a substantially decreased H4K16 acetylation in cells treated with DMOG under hypoxia, because associated chromatin remodelling can modulate HIF and NF-kB specific transcription, both shown to play a pivotal role in hypoxia-associated inflammation [20] [63] [80]. An interplay between a decrease in NADH, reduction of OxPhos, activation of glycolysis and increase in O 2 levels observed in the inflamed tissue upon treatment with DMOG, is still to be understood. "
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    ABSTRACT: Abnormal accumulation of oncometabolite fumarate and succinate is associated with inhibition of mitochondrial function and carcinogenesis. By competing with α-ketoglutarate, oncometabolites also activate hypoxia inducible factors (HIF), which makes oncometabolite mimetics broadly utilised in hypoxia research. We found that dimethyloxalylglycine (DMOG), a synthetic analogue of α-ketoglutarate, commonly used to induce HIF signalling, inhibits O2 consumption in cancer cell lines HCT116 and PC12, well before activation of HIF pathways. A rapid suppression of cellular respiration was accompanied by a decrease in histone H4 lysine 16 acetylation and not abolished by double knockdown of HIF-1α and HIF-2α. In agreement with this, production of NADH and state 3 respiration in isolated mitochondria were down-regulated by the de-esterified DMOG derivative, N-oxalylglycine. Exploring the roles of DMOG as a putative inhibitor of glutamine / α-ketoglutarate metabolic axis, we found that the observed suppression of OxPhos and compensatory activation of glycolytic ATP flux make cancer cells vulnerable to combined treatment with DMOG and inhibitors of glycolysis. On the other hand, DMOG treatment impairs deep cell deoxygenation in 3D tissue culture models, demonstrating a potential to relieve functional stress imposed by deep hypoxia on tumour, ischemic or inflamed tissues. Indeed, using a murine model of colitis, we found that O2 availability in the inflamed colon tissue rapidly increased after application of DMOG, which could contribute to the known therapeutic effect of this compound. Overall, our results provide new insights into the relationship between mitochondrial function, O2 availability, metabolic reprogramming and associated diseases. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 07/2015; 1847(10). DOI:10.1016/j.bbabio.2015.06.016 · 4.66 Impact Factor
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    • "These data suggest that HIF-mediated expression of CLDN1 might play an important role in barrier maintenance during an inflammatory insult. HIF has been extensively linked to beneficial outcomes in murine models of colitis (Karhausen et al., 2004; Cummins et al., 2008; Robinson et al., 2008). Although the endpoints of such signaling vary, significant emphasis has been placed on the barrier-protective aspects of hypoxia and HIF signaling (Colgan and Taylor, 2010; Glover and Colgan, 2011). "
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    ABSTRACT: Intestinal epithelial cells (IECs) are exposed to profound fluctuations in oxygen tension and have evolved adaptive transcriptional responses to a low-oxygen environment. These adaptations are mediated primarily through the hypoxia-inducible factor (HIF) complex. Given the central role of the IEC in barrier function, we sought to determine whether HIF influenced epithelial tight junction (TJ) structure and function. Initial studies revealed that short hairpin RNA-mediated depletion of the HIF1β in T84 cells resulted in profound defects in barrier and nonuniform, undulating TJ morphology. Global HIF1α chromatin immunoprecipitation (ChIP) analysis identified claudin-1 (CLDN1) as a prominent HIF target gene. Analysis of HIF1β-deficient IEC revealed significantly reduced levels of CLDN1. Overexpression of CLDN1 in HIF1β-deficient cells resulted in resolution of morphological abnormalities and restoration of barrier function. ChIP and site-directed mutagenesis revealed prominent hypoxia response elements in the CLDN1 promoter region. Subsequent in vivo analysis revealed the importance of HIF-mediated CLDN1 expression during experimental colitis. These results identify a critical link between HIF and specific tight junction function, providing important insight into mechanisms of HIF-regulated epithelial homeostasis.
    Molecular Biology of the Cell 06/2015; 26(12). DOI:10.1091/mbc.E14-07-1194 · 4.47 Impact Factor
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    • "In this regard, HIF-1a inhibition could be a potential strategy for limiting exacerbated responses, such as arthritis (Giaccia et al., 2003). Another approach consists of PHD inhibition, which has shown therapeutic potential in preclinical models of colitis (Cummins et al., 2008; Fraisl et al., 2009; Robinson et al., 2008). "
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    ABSTRACT: The hypoxic response in cells and tissues is mediated by the family of hypoxia-inducible factor (HIF) transcription factors; these play an integral role in the metabolic changes that drive cellular adaptation to low oxygen availability. HIF expression and stabilization in immune cells can be triggered by hypoxia, but also by other factors associated with pathological stress: e.g., inflammation, infectious microorganisms, and cancer. HIF induces a number of aspects of host immune function, from boosting phagocyte microbicidal capacity to driving T cell differentiation and cytotoxic activity. Cellular metabolism is emerging as a key regulator of immunity, and it constitutes another layer of fine-tuned immune control by HIF that can dictate myeloid cell and lymphocyte development, fate, and function. Here we discuss how oxygen sensing in the immune microenvironment shapes immunological response and examine how HIF and the hypoxia pathway control innate and adaptive immunity.
    Immunity 10/2014; 41(4):518-528. DOI:10.1016/j.immuni.2014.09.008 · 21.56 Impact Factor
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