Differentiation role of PARP‐1 in p65 NF‐kB translocation into nuclei of primary aortic smooth muscle cells in response to TNF, LPS or H2O2: Implication in atherosclerosis

Abstract

Using a mouse model of high fat diet (HF)-induced atherosclerosis, we report a correlation between DNA damage within atherosclerotic plaques, expression of NF-kB-dependent inflammatory factors and the activation of PARP-1 suggesting a role for PARP-1 in the onset of the disease. Administration of the PARP-1 inhibitor TIQ-A caused a reduction in size and changes in structure of atherosclerotic plaques after 12 weeks of HF diet. Plaques from TIQ-treated mice contained thicker fibrous caps with a high number of smooth muscle cells (SMCs) and atrophic foam cells with minimal macrophage recruitment. Using an in vitro cell culture model of vascular inflammation and fluorescently tagged p65 NF-kB, we show that the translocation of this transcription factor into nuclei of primary aortic SMC required PARP-1 expression in response to LPS or H2O2 but not in response to TNF. Similarly, degradation of I-kB alpha was defective in LPS or H2O2-treated but not in TNF-treated PARP-1−/− SMC. However, the TNF-triggered p65 NFkB translocation and I-kB alpha degradation did not induce expression of the NF-kB-dependent iNOS in PARP-1−/− SMC. These results demonstrate that p65 NF-kB translocation to nuclei and the concomitant degradation of I-kB alpha are not sufficient for expression of inflammatory factors but required expression of PARP-1. These results suggest a role for PARP-1 in the onset of atherosclerosis through a mediation of the signal transduction of NF-kB and the concomitant expression of inflammatory factors. Support: NIH-1P20RR18766 and HL072889 to H. B.