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Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages

Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Her...

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Autores principales: Sotoodehnejadnematalahi, Fattah, Staples, Karl J., Chrysanthou, Elvina, Pearson, Helen, Ziegler-Heitbrock, Loems, Burke, Bernard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461269/
https://www.ncbi.nlm.nih.gov/pubmed/26057378
http://dx.doi.org/10.1371/journal.pone.0125799
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author Sotoodehnejadnematalahi, Fattah
Staples, Karl J.
Chrysanthou, Elvina
Pearson, Helen
Ziegler-Heitbrock, Loems
Burke, Bernard
author_facet Sotoodehnejadnematalahi, Fattah
Staples, Karl J.
Chrysanthou, Elvina
Pearson, Helen
Ziegler-Heitbrock, Loems
Burke, Bernard
author_sort Sotoodehnejadnematalahi, Fattah
collection PubMed
description Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM), and, intriguingly, show that versican mRNA is up-regulated much more highly (>600 fold) by long term hypoxia (5 days) than by 1 day of hypoxia (48 fold). We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K), LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression.
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spelling pubmed-44612692015-06-16 Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages Sotoodehnejadnematalahi, Fattah Staples, Karl J. Chrysanthou, Elvina Pearson, Helen Ziegler-Heitbrock, Loems Burke, Bernard PLoS One Research Article Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM), and, intriguingly, show that versican mRNA is up-regulated much more highly (>600 fold) by long term hypoxia (5 days) than by 1 day of hypoxia (48 fold). We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K), LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression. Public Library of Science 2015-06-09 /pmc/articles/PMC4461269/ /pubmed/26057378 http://dx.doi.org/10.1371/journal.pone.0125799 Text en © 2015 Sotoodehnejadnematalahi et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sotoodehnejadnematalahi, Fattah
Staples, Karl J.
Chrysanthou, Elvina
Pearson, Helen
Ziegler-Heitbrock, Loems
Burke, Bernard
Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages
title Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages
title_full Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages
title_fullStr Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages
title_full_unstemmed Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages
title_short Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages
title_sort mechanisms of hypoxic up-regulation of versican gene expression in macrophages
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461269/
https://www.ncbi.nlm.nih.gov/pubmed/26057378
http://dx.doi.org/10.1371/journal.pone.0125799
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