Activation of non-ischemic, hypoxia-inducible signalling pathways up-regulate cytoprotective genes in the murine liver

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 2 h 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.

Role of cAMP-responsive Element-binding Protein (CREB)-regulated Transcription Coactivator 3 (CRTC3) in the Initiation of Mitochondrial Biogenesis and Stress Response in Liver Cells

“…Specific responses to stress in cellular compartments are mediated by distinct transducers. Nuclear translocation of heat shock factor (HSF), hypoxia-inducible factor (HIF), and nuclear respiratory factor-2 (Nrf-2) mediate heat shock (36), hypoxia-inducible (37), and oxidative stress responses in cytosol (38), and release of several transcription factors such as activating transcription factor 6 (ATF6) from ER controls the unfolded protein/ER response (39).…”

Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice

“…The HAL-induced hypoxia in HCC was further validated by examining the expression of two hypoxic markers, erythropoietin (EPO) (mRNA level) and HIF-1α (protein level) (17). The expression of both markers was elevated in the HCC in the left lobe 2 h after HAL, whereas those in the adjacent nontumorous liver and in the HCC in the right lobe did not change significantly ( Fig.…”

Morphology and Hemodynamics during Vascular Regeneration in Critically Ischemic Murine Skin Studied by Intravital Microscopy Techniques

“…Interstitial concentrations of pyruvate and lactate were determined as previously described [12,24,25,26]. The lactate-to-pyruvate ratio was calculated to assess the aerobic/anaerobic correlation.…”

“…Investigations were performed using an epiluminescence intravital microscope (Zeiss AxioplanI; Zeiss, Jena, Germany), as reported earlier [2,12,23,28]. Microscopic images were captured by a television camera (intensified CCD camera; Kappa Messtechnik, Gleichen, Germany), displayed on a television screen (Trinitron PVM-1454; Sony, Tokyo, Japan), and recorded on video (50 Hz; Panasonic AG-7350-SVHS, Tokyo, Japan) for subsequent off-line analysis with the help of a computer-assisted image analysis system (CapImage; Zeintl, Heidelberg, Germany) [29,30].…”

“…Various techniques have been used to demonstrate oxygen delivery [9], oxygen homeostasis or blood flow by dye diffusion [10], laser Doppler flowmetry [11], oxygen measurements [12,13] or microdialysis [14,15,16]. However, all these techniques have their limitations in assessing blood perfusion only indirectly.…”