title: Activation of non-ischemic, hypoxia-inducible signalling pathways up-regulate cytoprotective genes in the murine liver.
abstract: OBJECTIVE
  We investigated the molecular response of a non-ischemic hypoxic stress in the liver, in particular, to distinguish its hepatoprotective potential.
  
  
  METHODS
  The livers of mice were subjected to non-ischemic hypoxia by clamping the hepatic-artery (HA) for 2h while maintaining portal circulation. Hypoxia was defined by a decrease in oxygen saturation, the activation of hypoxia-inducible factor (HIF)-1 and the mRNA up-regulation of responsive genes. To demonstrate that the molecular response to hypoxia may in part be hepatoprotective, pre-conditioned animals were injected with an antibody against Fas (Jo2) to induce acute liver failure. Hepatocyte apoptosis was monitored by caspase-3 activity, cleavage of lamin A and animal survival.
  
  
  RESULTS
  Clamping the HA induced a hypoxic stress in the liver in the absence of severe metabolic distress or tissue damage. The hypoxic stimulus was sufficient to activate the HIF-1 signalling pathway and up-regulate hepatoprotective genes. Pre-conditioning the liver with hypoxia was able to delay the onset of Fas-mediated apoptosis and prolong animal survival.
  
  
  CONCLUSIONS
  Our data reveal that hepatic cells can sense and respond to a decrease in tissue oxygenation, and furthermore, that activation of hypoxia-inducible signalling pathways function in part to promote liver cell survival.
authors.affiliation: Clinic of Visceral and Transplantation Surgery, Department of Clinical Research, University of Bern, Murtenstrase 35, 3010 Bern, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Plock
authors.forename: Steffen
authors.initials: S
authors.lastname: Frese
authors.forename: Adrian
authors.initials: A
authors.lastname: Keogh
authors.forename: Sonja
authors.initials: S
authors.lastname: Bisch-Knaden
authors.forename: Erick
authors.initials: E
authors.lastname: Ayuni
authors.forename: Nadia
authors.initials: N
authors.lastname: Corazza
authors.forename: Christian
authors.initials: C
authors.lastname: Weikert
authors.forename: Stephan
authors.initials: S
authors.lastname: Jakob
authors.forename: Dominique
authors.initials: D
authors.lastname: Erni
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.forename: Thomas
authors.initials: T
authors.lastname: Brunner
authors.forename: Daniel
authors.initials: D
authors.lastname: Candinas
authors.forename: Deborah
authors.initials: D
authors.lastname: Stroka
mesh_terms: D000818:Animals; D019610:Cytoprotection / Q000235:genetics*; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000235:genetics*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D010101:Oxygen Consumption; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D051793:Hypoxia-Inducible Factor 1