PARP INHIBITION IN ATHEROSCLEROSIS AND ITS EFFECTS ON DENDRITIC CELLS, T CELLS AND AUTO-ANTIBODY LEVELS

Objective: Atherosclerosis is a chronic inflammatory process. Poly(ADP-ribose) polymerase-1 (PARP), a nuclear enzyme linked to DNA repair, has been shown to be involved in atherogenesis; however, the effects on dendritic cells, T cells and serum auto-antibody levels are not fully understood. Methods: Male Apoe(-/-) mice on a western diet were treated with the PARP inhibitor INO-1001 (n = 15), while the control group (n = 15) received 5% glucose solution for 10 weeks. Results: Inhibition of PARP markedly reduced atherosclerotic lesion development (p = 0.001). Immunohistochemistry and mRNA analysis revealed a reduced inflammatory compound inside the lesion. Focusing on dendritic cells, INO-1001 reduced number of cells (p = 0.04), grade of activation, represented by Il12 (p = 0.04) and Cd83 (p = 0.03), and grade of attraction, represented by Mip3 alpha (p = 0.02) in the plaque. Furthermore, INO-1001 decreased number of T lymphocyte (p = 0.003) in the lesion and grade of activation after stimulation with oxLDL, in vitro. Moreover, serum IgM antibody levels to oxLDL, were significantly lower in INO-1001 treated mice (p = 0.03). Conclusions: Functional blockade of PARP by INO-1001 reduces atherosclerotic lesion development. The anti-atherogenic effect is beside already known mechanisms also moderated due to modulation of DC and T cell invasion and activation, DC attraction as well as IgM antibody levels to oxLDL.