title: HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia.
abstract: Extracellular adenosine (Ado) has been implicated as central signaling molecule during conditions of limited oxygen availability (hypoxia), regulating physiologic outcomes as diverse as vascular leak, leukocyte activation, and accumulation. Presently, the molecular mechanisms that elevate extracellular Ado during hypoxia are unclear. In the present study, we pursued the hypothesis that diminished uptake of Ado effectively enhances extracellular Ado signaling. Initial studies indicated that the half-life of Ado was increased by as much as fivefold after exposure of endothelia to hypoxia. Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia. Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)-dependent repression of ENT1 during hypoxia. Using in vitro and in vivo models of Ado signaling, we revealed that decreased Ado uptake promotes vascular barrier and dampens neutrophil tissue accumulation during hypoxia. Moreover, epithelial Hif1alpha mutant animals displayed increased epithelial ENT1 expression. Together, these results identify transcriptional repression of ENT as an innate mechanism to elevate extracellular Ado during hypoxia.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Tübingen, Germany.
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Parween
authors.initials: P
authors.lastname: Abdulla
authors.forename: Edgar
authors.initials: E
authors.lastname: Hoffman
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hamilton
authors.forename: Dionne
authors.initials: D
authors.lastname: Daniels
authors.forename: Caroline
authors.initials: C
authors.lastname: Schönfeld
authors.forename: Michaela
authors.initials: M
authors.lastname: Löffler
authors.forename: German
authors.initials: G
authors.lastname: Reyes
authors.forename: Michael
authors.initials: M
authors.lastname: Duszenko
authors.forename: Jorn
authors.initials: J
authors.lastname: Karhausen
authors.forename: Andreas
authors.initials: A
authors.lastname: Robinson
authors.forename: Karen A
authors.initials: KA
authors.lastname: Westerman
authors.forename: Imogen R
authors.initials: IR
authors.lastname: Coe
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D033721:Equilibrative Nucleoside Transporter 1 / Q000096:biosynthesis*; D033722:Equilibrative-Nucleoside Transporter 2 / Q000096:biosynthesis*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D009504:Neutrophils / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; D051793:Hypoxia-Inducible Factor 1; C438649:SLC29A1 protein, human; D014665:Vasodilator Agents; D000241:Adenosine