Abstract 1685: Thieno[2,3-c]isoquinolin-5-one (TIQ-A), a Potent Poly(ADP-ribose) Polymerase Inhibitor, Promotes Atherosclerotic Plaque Regression in High Fat Diet-fed ApoE-deficient Mice: Effects on Inflammatory Markers and Lipid Content
Background: We recently showed that poly(ADP-ribose) polymerase (PARP) is activated within atherosclerotic plaques in an animal model of atherosclerosis and that PARP inhibition pharmacologically or by gene heterozygosity promotes factors of plaque stability by protecting smooth muscle cells and endothelial cells against pro-inflammatory agents. Based upon these observations, the current study, addresses the hypothesis that PARP inhibition may promote the regression of pre-established atherosclerotic plaques.
Methods: High-fat diet was fed to ApoE−/− mice for 12 weeks after which one group was administered potent PARP inhibitor, thieno[2,3-c]isoquinolin-5-one (TIQ-A), along with a regular diet for 4 weeks and another group was fed regular diet alone. Separate group of mice received high-fat diet with or without TIQ-A for 16 weeks to quantitatively determine the regression of plaque.
Results: High fat diet induced active atherosclerotic plaque formation which was partially reduced by TIQ-A in 16 weeks group. Interestingly, TIQ-A administration along with regular diet for 4 weeks further promoted significant regression of pre-established plaques than regular diet alone. Plaque regression with TIQ-A combined with regular diet was closely associated with a robust reduction in total and vLDL + LDL cholesterol. More importantly, plaques of TIQ-A-treated mice were highly enriched with collagen and smooth muscle cells, displayed a thick fibrous cap, and exhibited a marked reduction in CD68-positive macrophage recruitment and associated foam cell presence. These changes correlated with a significant decrease in the expression of MCP-1 and ICAM-1, potentially, as a result of a reduction in TNF expression in aorta.
Conclusion: PARP inhibition when combined with regular diet promotes the regression of previously established plaques, potentially through a reduction in inflammatory factors and serum lipid levels. The study suggests that PARP inhibition may prove beneficial not only in preventing atherogenesis but also in promoting the regression of existing plaques thus projecting PARP inhibition as viable therapeutic strategy.