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Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease

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Abstract

Inflammatory lesions, ischemic tissues, or solid tumors are characterized by the occurrence of severe tissue hypoxia within the diseased tissue. Subsequent stabilization of hypoxia-inducible transcription factors—particularly of hypoxia-inducible factor 1α (HIF1A)—results in significant alterations of gene expression of resident cells or inflammatory cells that have been recruited into such lesions. Interestingly, studies of hypoxia-induced changes of gene expression identified a transcriptional program that promotes extracellular adenosine signaling. Adenosine is a signaling molecule that functions through the activation of four distinct adenosine receptors—the ADORA1, ADORA2A, ADORA2B, and ADORA3 receptors. Extracellular adenosine is predominantly derived from the phosphohydrolysis of precursor nucleotides, such as adenosine triphosphate or adenosine monophosphate. HIF1A-elicited alterations in gene expression enhance the enzymatic capacity within inflamed tissues to produce extracellular adenosine. Moreover, hypoxia-elicited induction of adenosine receptors—particularly of ADORA2B—results in increased signal transduction. Functional studies in genetic models for HIF1A or adenosine receptors implicate this pathway in an endogenous feedback loop that dampens excessive inflammation and promotes injury resolution, while at the same time enhancing ischemia tolerance. Therefore, pharmacological strategies to enhance HIF-elicited adenosine production or to promote adenosine signaling through adenosine receptors are being investigated for the treatment of acute inflammatory or ischemic diseases characterized by tissue hypoxia.

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Acknowledgments

The present research work was supported by Grant D/10/52531 from the German Academic Exchange Service (DAAD) to J.M.P., a German Research Foundation (DFG) Grant (EH401/1-1) to H.E., an American Heart Association Grant to A.G., and National Heart Institute Grants R01-HL0921, R01-DK083385, and R01-HL098294 and a grant by the Crohn’s and Colitis Foundation of America (CCFA) to H.K.E.

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The authors have declared no conflict of interest.

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Authors and Affiliations

  1. Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado School of Medicine, 12700 East 19th Avenue, Research Complex 2, Room 7124, Mailstop B112, Aurora, CO, 80045, USA

    Jens M. Poth, Kelley Brodsky, Heidi Ehrentraut, Almut Grenz & Holger K. Eltzschig

  2. Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany

    Jens M. Poth & Heidi Ehrentraut

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  1. Jens M. Poth
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  2. Kelley Brodsky
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  3. Heidi Ehrentraut
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  4. Almut Grenz
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  5. Holger K. Eltzschig
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Correspondence to Holger K. Eltzschig.

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Poth, J.M., Brodsky, K., Ehrentraut, H. et al. Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease. J Mol Med 91, 183–193 (2013). https://doi.org/10.1007/s00109-012-0988-7

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  • DOI: https://doi.org/10.1007/s00109-012-0988-7

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