Activation of non-ischemic, hypoxia-inducible signalling pathways up-regulate cytoprotective genes in the murine liver.
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.
Plock
Jan
J
Clinic of Visceral and Transplantation Surgery, Department of Clinical Research, University of Bern, Murtenstrase 35, 3010 Bern, Switzerland.
Frese
Steffen
S
Keogh
Adrian
A
Bisch-Knaden
Sonja
S
Ayuni
Erick
E
Corazza
Nadia
N
Weikert
Christian
C
Jakob
Stephan
S
Erni
Dominique
D
Dufour
Jean-François
JF
Brunner
Thomas
T
Candinas
Daniel
D
Stroka
Deborah
D
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
D051793:Hypoxia-Inducible Factor 1