KEAP1型
上睑下垂
槲皮素
化学
巨噬细胞
氧化应激
甾醇调节元件结合蛋白
药理学
细胞生物学
生物化学
转录因子
生物
细胞凋亡
抗氧化剂
体外
程序性细胞死亡
基因
作者
Xing Luo,Xiuzhu Weng,Xiaoyi Bao,Xiaoxuan Bai,Ying Lv,Shan Zhang,Yuwu Chen,Changhui Zhao,Ming Zeng,Jianxin Huang,Biyi Xu,Thomas W. Johnson,Stephen J. White,Li Ji,Haibo Jia,Bo Yu
出处
期刊:Redox biology
[Elsevier]
日期:2022-11-01
卷期号:57: 102511-102511
被引量:31
标识
DOI:10.1016/j.redox.2022.102511
摘要
Natural antioxidants represented by quercetin have been documented to be effective against atherosclerosis. However, the related mechanisms remain largely unclear. In this study, we identified a novel anti-atherosclerotic mechanism of quercetin inhibiting macrophage pyroptosis by activating NRF2 through binding to the Arg483 site of KEAP1 competitively. In ApoE-/- mice fed with high fat diet, quercetin administration attenuated atherosclerosis progression by reducing oxidative stress level and suppressing macrophage pyroptosis. At the cellular level, quercetin suppressed THP-1 macrophage pyroptosis induced by ox-LDL, demonstrated by inhibiting NLRP3 inflammasome activation and reducing ROS level, while these effects were reversed by the specific NRF2 inhibitor (ML385). Mechanistically, quercetin promoted NRF2 to dissociate from KEAP1, enhanced NRF2 nuclear translocation as well as transcription of downstream antioxidant protein. Molecular docking results suggested that quercetin could bind with KEAP1 at Arg415 and Arg483. In order to verify the binding sites, KEAP1 mutated at Arg415 and Arg483 to Ser (R415S and R483S) was transfected into THP-1 macrophages, and the anti-pyroptotic effect of quercetin was abrogated by Arg483 mutation, but not Arg415 mutation. Furthermore, after administration of adeno associated viral vector (AAV) with AAV-KEAP1-R483S, the anti-atherosclerotic effects of quercetin were almost abolished in ApoE-/- mice. These findings proved quercetins suppressed macrophage pyroptosis by targeting KEAP1/NRF2 interaction, and provided reliable data on the underlying mechanism of natural antioxidants to protect against atherosclerosis.
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