HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

doi:10.1084/jem.20050177

Published 5 December 2005. doi:10.1084/jem.20050177
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 11, 1493-1505

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HIF-1–dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

Holger K. Eltzschig¹, Parween Abdulla³, Edgar Hoffman¹, Kathryn E. Hamilton⁴, Dionne Daniels⁴, Caroline Schönfeld², Michaela Löffler¹, German Reyes³, Michael Duszenko², Jorn Karhausen¹, Andreas Robinson⁴, Karen A. Westerman⁵, Imogen R. Coe³, and Sean P. Colgan⁴

¹ Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital
² Physiologisch-chemisches Institut der Universität Tübingen, D-72076, Tübingen, Germany
³ Department of Biology, York University, Toronto M3J 1P3, Canada
⁴ Center for Experimental Therapeutics and Reperfusion Injury, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
⁵ Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Sean P. Colgan: colgan{at}zeus.bwh.harvard.edu

Extracellular adenosine (Ado) has been implicated as centralsignaling molecule during conditions of limited oxygen availability(hypoxia), regulating physiologic outcomes as diverse as vascularleak, leukocyte activation, and accumulation. Presently, themolecular mechanisms that elevate extracellular Ado during hypoxiaare unclear. In the present study, we pursued the hypothesisthat diminished uptake of Ado effectively enhances extracellularAdo signaling. Initial studies indicated that the half-lifeof Ado was increased by as much as fivefold after exposure ofendothelia to hypoxia. Examination of expressional levels ofthe equilibrative nucleoside transporter (ENT)1 and ENT2 revealeda transcriptionally dependent decrease in mRNA, protein, andfunction in endothelia and epithelia. Examination of the ENT1promoter identified a hypoxia inducible factor 1 (HIF-1)–dependentrepression of ENT1 during hypoxia. Using in vitro and in vivomodels of Ado signaling, we revealed that decreased Ado uptakepromotes vascular barrier and dampens neutrophil tissue accumulationduring hypoxia. Moreover, epithelial Hif1 ${alpha}$ mutant animals displayedincreased epithelial ENT1 expression. Together, these resultsidentify transcriptional repression of ENT as an innate mechanismto elevate extracellular Ado during hypoxia.

Abbreviations used: Ado, adenosine; ChIP, chromatin immunoprecipitation;ENT, equilibrative nucleoside transporter; HIF-1, hypoxia induciblefactor 1; HMEC, human microvascular endothelial cells; HRE,hypoxia-responsive element; MPO, myeloperoxidase.

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