PolyADPRibose Polymerase Regulates Gene Expression and Mononuclear Cell Recruitment
Using pharmacological inhibitors of PARP, it has been demonstrated (as briefly mentioned earlier) that the activity of PARP is required for the expression of the MHC class II gene, DNA methyltransferase gene, protein kinase C (PKC), collagenase, ICAM-1, and (iNOS) (10-14). An oligonucleotide microarray analysis identified multiple genes that appear to be under the control of PARP-1 in resting cells (14) and even more genes are affected under conditions of immunostimulation (30). A distinct mode of inhibition of the expression of pro-inflammatory mediators by inhibition of PARP relates to the regulation of NF-kB activation. It is unclear whether PARP catalytic activity vs PARP as a structural protein plays the most important role in its stimulatory role on NF-kB activation (31,32), it may well be that both mechanisms can be involved under certain experimental conditions. Pharmacological evidence supports the view that PARP also regulates the c-fos—AP-1 transcription system and the activation of mitogen-activated protein kinase (33,34). From the above experimental data it appears that PARP, via a not yet fully characterized mechanism, regulates the expression of a variety of genes, with
the net result that PARP inhibition or PARP genetic inactivation results in the downregulation of a variety of important pro-inflammatory mediators and pathways.
The PARP-mediated pathway of cell necrosis and the PARP-mediated pathway of inflammatory signal transduction and gene expression may be interrelated in pathophysiological conditions. Oxidant stress can generate DNA single-strand breaks. DNA strand breaks then activate PARP, which in turn potentiates NF-kB activation and AP-1 expression, resulting in greater expression of the AP-1 and NF-kB-dependent genes, such as the gene for ICAM-1, and chemokines such as MIP-1 a and cytokines such as tumor necrosis factor-a. Chemokine generation, in combination with increased endothelial expression of ICAM-1, recruits more activated leukocytes to inflammatory foci, producing greater oxidant stress. It is possible that a low-level, localized inflammatory response may be beneficial in recruiting mononuclear cells to an inflammatory site. However, in many pathophysiological states the above described feedback cycles amplify themselves beyond control.
Overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury (13,35), reperfusion injury after heart transplantation (36), chronic heart failure (37,38), stroke (39), circulatory shock (32,40-42), and the process of autoimmune P-cell destruction associated with DM (43,44). Activation of PARP and beneficial effect of various PARP inhibitors have been demonstrated in various forms of endothelial dysfunction such as the one associated with circulatory shock, hypertension, atherosclerosis, preeclampsia, and aging (40,45-48). Furthermore, recent evidence demonstrates that activation of PARP importantly contributes to the development of cardiac and endothelial dysfunction in various experimental models of diabetes and also in humans (49-52). The following chapter will discuss this subject in detail.
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