title: Equilibrative nucleoside transporter (ENT)-1-dependent elevation of extracellular adenosine protects the liver during ischemia and reperfusion.
abstract: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality of hepatic surgery and during liver transplantation. Previous studies implicated extracellular adenosine signaling in liver protection. Based on the notion that extracellular adenosine signaling is terminated by uptake from the extracellular towards the intracellular compartment by way of equilibrative nucleoside transporters (ENTs), we hypothesized a functional role of ENTs in liver protection from ischemia. During orthotopic liver transplantation in humans, we observed higher expressional levels of ENT1 than ENT2, in conjunction with repression of ENT1 and ENT2 transcript and protein levels following warm ischemia and reperfusion. Treatment with the pharmacologic ENT inhibitor dipyridamole revealed elevations of hepatic adenosine levels and robust liver protection in a murine model of liver ischemia and reperfusion. Studies in gene-targeted mice for Ent1 or Ent2 demonstrated selective protection from liver injury in Ent1(-/-) mice. Treatment with selective adenosine receptor antagonists indicated a contribution of Adora2b receptor signaling in ENT-dependent liver protection.
  
  
  CONCLUSIONS
  These findings implicate ENT1 in liver protection from ischemia and reperfusion injury and suggest ENT inhibitors may be of benefit in the prevention or treatment of ischemic liver injury.
authors.affiliation: Division of Transplant Surgery, Department of Surgery, University of Colorado, Aurora, CO.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Zimmerman
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Tak
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Ehrentraut
authors.forename: Maria
authors.initials: M
authors.lastname: Kaplan
authors.forename: Antasia
authors.initials: A
authors.lastname: Giebler
authors.forename: Tingting
authors.initials: T
authors.lastname: Weng
authors.forename: Doo-Sup
authors.initials: DS
authors.lastname: Choi
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Igal
authors.initials: I
authors.lastname: Kam
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
mesh_terms: D000241:Adenosine / Q000502:physiology*; D000818:Animals; D004176:Dipyridamole / Q000494:pharmacology; D033721:Equilibrative Nucleoside Transporter 1 / Q000502:physiology*; D033722:Equilibrative-Nucleoside Transporter 2 / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008099:Liver / Q000098:blood supply*; D016031:Liver Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D043704:Receptor, Adenosine A2B / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043704:Receptor, Adenosine A2B; C438654:SLC29A2 protein, human; D004176:Dipyridamole; D000241:Adenosine