Ogg1-Dependent DNA Repair Regulates NLRP3 Inflammasome and Prevents Atherosclerosis
Rationale: Activation of NLRP3 inflammasome mediating IL-1β secretion has emerged as an important component of inflammatory processes in atherosclerosis. Mitochondrial DNA (mtDNA) damage is detrimental in atherosclerosis and mitochondria are central regulators of the NLRP3 inflammasome. Human atherosclerotic plaques express increased mtDNA damage. The major DNA glycosylase OGG1, is responsible for removing the most abundant form of oxidative DNA damage.
Objective: To test the role of OGG1 in development of atherosclerosis in mouse.
Methods and Results: We observed that Ogg1 expression decreases over time in atherosclerotic lesion macrophages of Ldlr KO mice fed a western diet. Ogg1-/-Ldlr-/- mice fed a western diet resulted in an increase in plaque size and lipid content. We found increased oxidized mtDNA, inflammasome activation, and apoptosis in atherosclerotic lesions and also higher serum IL-1β and IL-18 in Ogg1-/-Ldlr-/- mice compared with Ldlr-/-. Transplantation with Ogg1-/- bone marrow (BM) into Ldlr-/- mice led to larger atherosclerotic lesions and increased IL-1β production. However, transplantation of Ogg1-/-Nlrp3-/- BM reversed the Ogg1-/- phenotype of increased plaque size. Ogg1-/- macrophages showed increased oxidized mtDNA and had greater amounts of cytosolic mtDNA and cytochrome c, increased apoptosis, and more IL-1β secretion. Finally, we found that proatherogenic miR-33 can directly inhibit human OGG1 expression and indirectly suppress both mouse and human OGG1 via AMPK.
Conclusions: OGG1 plays a protective role in atherogenesis by preventing excessive inflammasome activation. Our study provides insight into a new target for therapeutic intervention based on a link between oxidative mtDNA damage, OGG1, and atherosclerosis via NLRP3 inflammasome.
- Received January 15, 2016.
- Revision received June 23, 2016.
- Accepted July 6, 2016.