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.

Hypoxia and Hypoxia Inducible Factors: Diverse Roles in Liver Diseases

“…Hepatic IR has been described to up‐regulate the HIF target VEGF 21. Unsurprisingly, HIF1α tends to accumulate during ischemia, but HIF1α DNA binding has been shown to decrease during reperfusion 22. Some data suggest that HIF1α‐dependent up‐regulation of the transferrin gene contributes to reactive species formation and liver injury in reperfusion, likely through iron‐dependent reactive species accumulation 23.…”

Hypoxia-Reoxygenation; A Potential Source of Placental Oxidative Stress in Normal Pregnancy and Preeclampsia

“…[75][76][77][78] The downstream effects include the expression of glycolytic enzymes, proinflammatory cytokines, such as tumour necrosis factor alpha (TNF␣) and interleukins (IL-1␤, IL-6 and IL-8), and their receptors. In the last few years great advances have been made in our understanding of how cells regulate their responses to oxygen, and the identification of redox-sensitive transcription factors has been central to this progress.…”

Heat shock enhances CMV-IE promoter-driven metabotropic glutamate receptor expression and toxicity in transfected cells

“…Although a direct effect of HS factors on the CMV-IE promoter cannot be excluded, as a considerable homology to the HS element core consensus (GA--TCC) within 18 bp elements in IE enhancer has been pointed out (Geelen et al, 1987), HS might regulate its activity indirectly, through induction of various transcription factors including those activating the CMV-IE promoter. For example, HS activates AP-1 in variety of cell types (Sikora et al, 1993; Harada et al, 2003), CREB in rat intestinal epithelial cells (Harada et al, 2003), C/EBP-beta in human intestinal epithelial cells (Hungness et al, 2002) in vitro, and AP-1 and CREB (Tacchini et al, 1999) in rat liver in vivo. The effect of HS on NF-kappaB is somewhat controversial and depends on cell type and conditions, since both activation (Sikora et al, 1993) and inhibition (Santoro, 2000) have been reported.…”