Activation of non-ischemic, hypoxia-inducible signalling pathways up-regulate cytoprotective genes in the murine liver.
J Hepatol
; 47(4): 538-45, 2007 Oct.
Article
em En
| MEDLINE
| ID: mdl-17599631
ABSTRACT
BACKGROUND/AIMS:
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.
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Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
/
Citoproteção
/
Fator 1 Induzível por Hipóxia
/
Fígado
/
Hipóxia
Limite:
Animals
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article