This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our long-term objective is to establish the role of PARP-1 in the pathogenesis of atherosclerosis and to propose the inhibition of this enzyme as a viable strategy for prevention and/or treatment atherosclerosis. Inflammation and inflammation associated cell death are becoming central features of the pathogenesis of this disease. Oxygen (ROS) and nitrogen (RNS) radicals contribute to inflammation by damaging DNA, which, in turn, results in the activation of PARP-1. The depletion both NAD and ATP as a result of persistent activation of PARP-1 leads to a cellular energy crisis and, eventually, to cell death. The activation of PARP-1 has been associated in animal models with the pathogenesis of several diseases or conditions, which involve radical-induced cell damage as an important factor in their initiation or progression. The inhibition of PARP-1 attenuates the symptoms of these diseases. We proposed to test the hypothesis that reactive species generated during atherosclerosis induce DNA damage and persistent activation of PARP-1 in macrophages and vascular epithelial and smooth muscle cells, resulting in the depletion of cellular energy reserves and vascular inflammation contributing to plaque instability. After the complete establishment of the mouse (ApoE-/-) model of high fat diet-induced atherosclerosis, we were able to determine that inhibition of PARP-1 by TIQ (a potent inhibitor of PARP-1) moderately reduced plaque size after 8 weeks of high fat diet. However, the structure of the plaques was markedly different from those observed in mice that received no inhibitor. PARP-1 inhibition seems to promote factors of atherosclerotic plaque stability. We have generated the ApoE/PARP-1 double knockout mice, which will allows us to pursue our studies and confirm our results with TIQ. We have also established a cell culture model of plaque instability, which allowed us to determine that PARP-1 promotes death of vascular cells in response to oxidative stress. We have also made some progress into determining the role of PARP-1 in the expression of NF-kB-regulated inflammatory genes and have established a foundation that will permit us to directly examine the potential interaction between PARP-1 and NF-kB. In the next year, we will be able to direct our efforts in all thre
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