Transcription

A reprogramming of the expression of several genes can occur in the cell in response to stress contributing to cell defense and survival. Several regulators of transcription are implicated in this response.

NF-xB is a pleiotropic transcription factor that responds rapidly to a variety of stimuli including cytokines, endotoxin and oxidative stress. NF-xB controls both cell survival and cell death. Ligand binding to cell surface receptor leads to the phosphorylation of the inhibitor protein IkB and release of the sequestered NF-xB in the cytosol. Figure 21. NF-xB then translocates into the nucleus followed by phosphorylation and binds to the promoter region of the target gene. Figure 21. Genes regulated by this transcription factor include the inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), manganese-conjugated superoxide dismutase (MnSOD), anti-apoptotic proteins, such as Bcl-2, inhibitor of apoptosis factors (IAFs) and members of the cytokine family (e.g TNF-a), interleukins (e.g IL-1 and IL-6), cell adhesion molecules (ICAM, VCAM, selectins), Fas ligand and other transcription factors (p53).162 Figure 21.

NF-xB activation occurs shortly after initiation of ischemia and is augmented by reperfusion in isolated heart models of ischemia and reperfusion. In in vivo models of coronary occlusion, NF-xB activation occurs at reperfusion in two phases; The first phase is at an early time of reperfusion due to oxidative stress and the second phase occurs later probably due to circulation of the de novo synthesized cytokines and interleukins. Studies with NF-kB decoys, blocking NF-xB activity, show a detrimental effect of NF-xB on the ischemic tolerance of the heart.163 Furthermore, genetic blockade of NF-xB reduced infarct size in murine heart after ischemia and reperfusion. However, transient increased activity of the NF-xB has been linked to cardioprotection. Binding activity of NF-xB is significantly increased by brief episodes of ischemia and reperfusion (ischemic preconditioning) and is attenuated by perfusing the hearts with a NF-xB blocker (SN-50) with subsequent loss of the preconditioning effect.164

AP-1 is a transcription factor for a variety of genes and seems to play an important role in cellular responses to stress. The binding site of AP-1 is recognized by Jun family

Figure 21. Schematic of activation of the NF-xB transcription factor. Phosphorylation of the inhibitor protein IkB results in release of the sequestered NF-xB to the cytosol. NF-xB then translocates into the nucleus followed by phosphorylation and binds to the promoter region of the target gene. NF-xB transcription factor can regulate the transcription of either survival or pro-death genes See text for more detailed explanation.

Ischemia

Ischemia

m-RNA

Protein Synthesis

Figure 21. Schematic of activation of the NF-xB transcription factor. Phosphorylation of the inhibitor protein IkB results in release of the sequestered NF-xB to the cytosol. NF-xB then translocates into the nucleus followed by phosphorylation and binds to the promoter region of the target gene. NF-xB transcription factor can regulate the transcription of either survival or pro-death genes See text for more detailed explanation.

Cytokines Chemokines INOS ICAM-1 Anliapoptotic Acute phase COX2 VCAM-1 Factors proteins MnSOD ELAM-1

Protein Synthesis

Cytokines Chemokines INOS ICAM-1 Anliapoptotic Acute phase COX2 VCAM-1 Factors proteins MnSOD ELAM-1

member homodimers and Jun/Fos family member heterodimers. The balance between Jun and Fos is critical for gene expression. Ischemia and reperfusion induces the activation of AP-1. When the heart is preconditioned to ischemic stress by short episodes of ischemia and reperfusion, AP-1 activation is reduced, reviewed by Das.165

p53 is a tumor suppressor protein and transcription factor that is activated by various stresses. p53 is known to promote apoptosis and this probably involves Bax and a series of p53 inducible genes signaling through Fas related pathways or caspases. Ischemia and reperfusion increases the activity of p53. Such an increase in p53 is prevented in ischemically adapted heart (ischemic preconditioning).165

GATA-4 is a member of the GATA family of zinc finger transcription factors which plays an important role in transducing nuclear events that modulate cell lineage differentiation during development. GATA-4 has been linked to cell survival and GATA-4 downregulation may be involved in the mechanism of the induction of cardiac myocyte apoptosis. In an isolated rat heart preparation, ischemia and reperfusion decrease GATA-4 DNA binding activity and GATA-4 mRNA. In contrast, in preconditioned hearts, GATA-4 DNA binding activity was increased in response to subsequent ischemia and reperfusion, indicating a cardioprotective role for GATA-4.166

2.4.1 Hypoxia inducible factor

Oxygen sensing and response to changes in the concentration of oxygen is a fundamental property of cell physiology. Lack of oxygen results in several adaptive responses in the cell, a process that is largely controlled by a transcription factor, known as hypoxia inducible factor (HIF-1). This factor consists of two subunits; the hypoxia regulated alpha subunit (HIF-1 a) and the oxygen insensitive HIF-1 (3 subunit. The activity of HIF-1 is predominantly regulated via stability of its a-subunit. Under normoxic conditions, HIF-1 a protein turns over rapidly and steady state levels are often below the detection limit. HIF-1 p is constitutively present. HIF-1 a destruction is accomplished by a family of enzymes sensitive to oxygen (PHDs). Subsequently, a E3-ubiquitin ligase complex containing the von Hippel Lindau protein (pVHL) facilitates HIF-1 a ubiq-uitination which is then recognized and degraded by the 26S proteasome. Figure 22. Oxygen deficiency attenuates PHD activity, prevents pVHL and proteosomal degradation and increases HIF-la accumulation.167 Figure 22. Non hypoxia stimuli also lead to the induction and activation of HIF-la. Growth factors, cytokines, vascular hormones and viral proteins are shown to induce HIF-1. Contrary to hypoxia, stabilization of HIF-1 a does not play a role in the non hypoxic induction of HIF-1 a and the degradation of HIF-la is not inhibited under non hypoxic activation of HIF-la. This process leads to the increased translation rate of the HIF-la protein and the PI3K pathway and its downstream effectors mTOR and p70S6K are involved.168 HIF-la activation leads to the transcription of genes encoding for erythropoietin (EPO), vascular endothelial growth factor (VEGF), insulin growth factor (IGF), glucose transporters (GLUT) and glycolytic enzymes. Figure 23. Such changes may favor cell survival under conditions of low oxygen tension. The impact of HIF-la in respect to its pro- vs anti-apoptotic role remains elucive. HIF-la can interact with the pro-apoptotic transcription factor p53 which is hypoxia inducible and the induction of HIF-la transcriptional activity in the early phase of hypoxia serves a protective role. With time progressing, inhibition of HIF-la and further induction of p53 may contribute to cell death.169

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