PARP1 Induced Changes in Gene Expression The Transcriptional Hypothesis

As mentioned before, the neuroprotective effect obtained by suppression of poly(ADP-ribosyl)ation in the ischemic brain might be related to changes in ischemia-induced gene expression profiles. Numerous findings establish a role of PARP-1 in nuclear functioning under homeostatic conditions, and imply that inhibition of PAR formation significantly affects ongoing transcription, the gene expression profile and resistance to stress. The role of PARP-1 in regulating transcription led to the formulation of the "transcriptional hypothesis" (Chiarugi 2002b). This pathogenetic interpretation states that some of the neurotoxic effects of PAR formation within the brain are transcription-dependent and related to changes in ischemia-induced gene expression profile.

Pioneering work by Poirier and associates demonstrates that PAR unravels chromatin superstructure (de Murcia et al. 1986, 1988; Poirier et al. 1982). Further studies also report a key role of the polymer in regulating histone H1 shuttling on chromatin fibers (Althaus et al. 1990), as well as gene transcription (D'Amours et al. 1999; Kraus and Lis 2003; Ziegler and Oei 2001). Indeed, PARP-1 has been identified as the previously described transcriptional coactiva-tor TFIIC (Slattery et al. 1983), and PARP-1 activity regulates expression of iNOS (Le Page et al. 1998), chemokines (Nirodi et al. 2001) and integrins (Ullrich et al. 2001b). Consistently, recent reports demonstrate that PARP-1 binding to promoter elements (Akiyama et al. 2001; Butler and Ordahl 1999; Nirodi et al. 2001), specific DNA superstructures (Kun et al. 2002) and to RNA-polymerase-II (Carty and Greenleaf 2002) is of relevance to chromatin organization and transcription. Indeed, PARP-1 is a key regulator of numerous transcription factors, including NF-kB (Chiarugi and Moskowitz 2003; Hassa et al. 2001; Hassa and Hottinger 1999; Oliver et al. 1999), AP-1 (Chiarugi 2002a; Ha et al. 2002; Zingarelli et al. 2004) and p53 (Agarwal et al. 1997; Schmid et al. 1999; Wang et al. 1998; Wesierska-Gadek et al. 1996; Wesierska-Gadek and Schmid

  1. Of note, inhibition of these trans-activating factors affords protection from ischemic brain injury (for review see (Chiarugi 2002b; Lo et al. 2003). Also, NF-kB and AP1 are central in activation of microglia and astrocytes and ensuing release of pro-inflammatory, neurotoxic mediators during post-ischemic brain damage (Feuerstain et al. 1998; Mattson et al. 2000; Mattson and Camandola
  2. Accordingly, inhibition of PARP-1 activity by different means impairs glia activation and ensuing neurodegeneration (Chiarugi and Moskowitz 2003; Ha et al. 2002; Nakajima et al. 2004b; Ullrich et al. 2001b).

In agreement with this assumption, inhibition of PARP-1 reduces expression of pro-inflammatory mediators such as CD11b, ICAM-1 and COX2 in the peri-infarcted region in the rat brain (Koh et al. 2004). Consistently, a recent study reports that the potent PARP-1 inhibitor PJ34 reduces ischemia-induced iNOS expression in the brain of mice subjected to 20 min MCAo/72 h reperfusion. Accordingly, treatment with PJ34 (25 mg/Kg) also decreased the raised levels of TNF-a protein and of mRNAs for TNF-a, IL-6, ICAM-1 and E-selectin in brain tissue after focal cerebral ischemia (Haddad et al. 2006). Finally, a recent study by Lenzser et al. (Lenzser et al. 2007) investigates the contribution of PARP activation to blood-brain barrier (BBB) disruption and edema formation after reperfusion in a in vivo model of global cerebral ischemia. The permeability of the BBB increases after ischemia-reperfusion compared with the nonischemic animals after 24 and 48 h reperfusion. The administration of the potent PARP inhibitor PJ34 (10 mg/kg), before ischemia, attenuates this increase and decreases brain edema seen at 48 h. PARP inhibition also reduces neutrophil infiltration and decreases ICAM-1 expression, a marker of leukocyte infiltration into the brain, at both 24 and 48 h. Importantly, a recent study reports that the activation of PARP-1 also regulates the translocation of HMGB-1 from the nucleus to the cytosol. HMGB-1 is a nuclear protein, highly expressed in the adult mouse brain, that when released into the extracellular space can elicit a potent inflammatory response (Scaffidi et al. 2002).

Indeed, the extracellular presence of recombinant HMGB1 increases excitotoxic and ischemic neuronal death in vitro. In addition, brain microinjection of HMGB1 increases the transcript levels of pro-inflammatory mediators and sensitizes the tissue to the ischemic injury (Faraco et al. 2007). Importantly, down-regulation of HMGB1 brain levels by siRNA correlates with diminished infarct volumes in the rat (Kim et al. 2006). Following N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG) treatment, translocation of HMGB-1 is observed in wild-type cells, whereas HMGB-1 remained nuclear in mouse embryonic fibroblasts lacking PARP-1; thus, these results suggests a role for PARP-1 in mediating relocalization of pro-inflammatory molecules in cells that have sustained DNA damage (Ditsworth et al. 2007). However, the PARP inhibitor PJ34 does not affect extracellular release of HMGB-1 from both neurons and astrocytes exposed to necrotic stimuli, indicating that poly (ADP-ribosyl)ation does not regulate HMGB-1 release during necrosis, at least in these cell types (Faraco et al. 2007). These results taken together highlight the significance of transcriptional regulation by PARP-1 in stroke pathogen-esis, and suggest that the remarkable stroke neuroprotection afforded by inhibitors of PARP-1 activity is related, at least in part, to changes in gene expression profiles in the ischemic brain tissue (Chiarugi 2002b; Skaper 2003a, 2003b).

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