Abstract 2: Ogg1 Plays A Protective Role In Diet Induced Atherosclerosis in LDLR KO mice.

Introduction: In human atherosclerosis, mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall, suggesting the importance of DNA damage repair enzymes. Mitochondria are a central regulator of NLRP3 function, which is a sensor of specific pathogen, host, and environmental danger molecules. Oxidized mtDNA can bind to and activate the NLRP3 inflammasome, which cleaves and activates interleukin-1β (IL-1β) and IL-18, cytokines that are pro-atherogenic. Ogg1, an oxoguanine glycosylase, can repair oxidized DNA. Objective: To assess the importance of the oxidative DNA damage repair gene, Ogg1, in atherogenesis. Methods and Results: To investigate the role of Ogg1 in atherogenesis, we generated Ogg1-/-Ldlr-/- mice. These mice had significantly larger plaques and greater lipid content in the aorta and the aortic root. Elevated levels of 8-OH-dG (a marker of oxidative DNA damage), Caspase-1 activation by FLICA staining, and apoptosis by TUNEL staining, were increased in Ogg1-/-Ldlr-/- animals compared with Ldlr-/- controls. Despite similar concentrations of plasma cholesterol, triglyceride, lipoprotein profile, glucose, insulin resistance, and body weight gain after 16 weeks high fat diet, serum MCP-1 was higher in Ogg1-/-Ldlr-/- mice compared with Ldlr-/- mice. Transplantation with Ogg1-/- bone marrow (BM) into irradiated recipient Ldlr-/- mice also resulted in an increase in atherosclerotic lesion size, 8-OH-dG accumulation, and IL-1β production in aortic tissue compared with control chimeric mice. However, Ogg1-/-/Nlrp3-/- BM transplanted into Ldlr-/- mice did not lead to acceleration of atherogenesis, suggesting that Ogg1 deficiency-induced acceleration of atherosclerosis was mediated by the NLRP3 inflammasome. Indeed, analysis of Ogg1-/- macrophages found a significant increase in caspase-1 activation and IL-1β secretion in these cells. Thus Ogg1 activity is anti-atherogenic. Conclusions: Our study provides direct evidence of a link between mtDNA damage, DNA damage repair enzyme OGG1, and atherosclerosis through increased inflammation via the NLRP3 inflammasome. These new data suggest that therapeutics designed to limit mtDNA damage may provide protection from atherosclerotic lesion development.