Differential activation of some transcription factors during rat liver ischemia, reperfusion, and heat shock

Abstract

Cells respond to external stimuli by changes in gene expression that are largely dependent on transcription factors (TFs). We studied the behavior of some TFs in rat liver during ischemia, postischemic reperfusion, and heat shock. Knowledge of the conditions at the end of ischemia is essential to understand changes occurring at reperfusion. The TFs investigated are known to be typically responsive to heat shock (HSF), hypoxia (HIF-1), pro- and antioxidant conditions (AP-1), or to various environmental changes (HNF-1 and ATF/CREB family). The most relevant new information includes the following: 1) Liver ischemia activates extremely rapidly the DNA binding capacity of HSF, soon followed by analogous activation of HIF-1 and AP-1. 2) After a certain lag time from the activation of HIF-1, mRNAs accumulate for two glycolytic enzymes, in particular Aldolase A and Heme Oxygenase 1, which contain HIF-1 sequences in their promoters. 3) Reperfusion, which is known to further increase the binding of HSF and to induce NFkappaB binding, abrogates or decreases the binding of HIF-1 and AP-1, stimulated by ischemia, and activates the binding of ATF/CREB. Later on, a second peak of AP-1 binding is induced. 4) Heat shock activates both ischemia-responsive and reperfusion-responsive TFs. 5) Preliminary experiments of supergelshift reveal that the activation of AP-1 at reperfusion or upon heat shock may result from the different involvement of the component subunits.

Transferrin receptor gene expression and transferrin-bound iron uptake are increased during postischemic rat liver reperfusion

“…43 The present work extends our previous findings, 21 showing that activation of another transcription factor (i.e., HIF-1) may be important. The role of HIF-1 activation in the pathogenesis of liver injury induced by ischemiareperfusion remains to be experimentally established but a pleiotropic effect could be envisaged.…”

“…Partial liver ischemia was induced, under light ether anesthesia, by occlusion of the hilar pedicle of the left lateral and median lobes with a small surgical clamp for different periods of time. 18,21 To induce reperfusion after non-necrogenic ischemia, the rats were reoperated after 1 hour of ischemia to remove the clamp and killed after different periods of restoration of the blood supply. Sham operation (SH) consisted in laparotomy and liver manipulation under ether anesthesia.…”

Liver Ischemia and Ischemia–Reperfusion Induces and Trafficks the Multi-specific Metal Transporter Atp7b to Bile Duct Canaliculi: Possible Preferential Transport of Iron into Bile

“…We also have data showing significant increases in the expression of HIF-1α after 90 min of liver ischemia alone and I/R (data not shown). Induction of HIF-1 subunits has been reported with liver I/R [35][36][37]. If Atp7b protein level is enhanced by HIF-1 binding to the 3′ enhancer sequence of the Atp7b gene, as reported for erythropoietin, tyrosine hydroxylase, and vascular endothelial growth factor, then this would correspond with the immediate reduction of Atp7b protein levels observed with reperfusion in this study (Fig.…”

Systematic review with meta-analysis: HIF-1α attenuates liver ischemia–reperfusion injury

“…In animal hypoxia models, oxygen concentration was varied from 0% to 21% (asphyxia, hypoxia, and normoxia) with time spans from acute hypoxia to tolerant hypoxia. In 21 IR animal models, 11 adopted 70% liver (left and middle lobe) IR (I: 1-6 h, R: 0.5-12 h) [15,16,23,24,36,37,39,43,46,47,51], 4 liver transplantation induced IR (I: 6-24 h, R: 2 h-14 d) [18,19,44,50] …”