吡喃结构域
炎症体
低密度脂蛋白受体
DNA糖基化酶
生物
线粒体DNA
分子生物学
癌症研究
炎症
DNA损伤
脂蛋白
免疫学
内分泌学
生物化学
DNA
基因
胆固醇
作者
Gantsetseg Tumurkhuu,Kenichi Shimada,Jargalsaikhan Dagvadorj,Timothy R. Crother,Wenxuan Zhang,Daniel Luthringer,Roberta A. Gottlieb,Shuang Chen,Moshe Arditi
标识
DOI:10.1161/circresaha.116.308362
摘要
Rationale: Activation of NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediating interleukin (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 nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3 inflammasome. Human atherosclerotic plaques express increased mtDNA damage. The major DNA glycosylase, 8-oxoguanine glycosylase (OGG1), is responsible for removing the most abundant form of oxidative DNA damage. Objective: To test the role of OGG1 in the development of atherosclerosis in mouse. Methods and Results: We observed that Ogg1 expression decreases over time in atherosclerotic lesion macrophages of low-density lipoprotein receptor ( Ldlr ) knockout 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 than in Ldlr −/− . Transplantation with Ogg1 −/− bone marrow into Ldlr −/− mice led to larger atherosclerotic lesions and increased IL-1β production. However, transplantation of Ogg1 −/− Nlrp3 −/− bone marrow 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 AMP-activated protein kinase. 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.
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