Reciprocal regulation of NRF2 by autophagy and ubiquitin-proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles

作者全名："Li, Na; Du, Hang; Mao, Lejiao; Xu, Ge; Zhang, Mengling; Fan, Yinzhen; Dong, Xiaomei; Zheng, Lijun; Wang, Bin; Qin, Xia; Jiang, Xuejun; Chen, Chengzhi; Zou, Zhen; Zhang, Jun"

作者地址："[Li, Na; Mao, Lejiao; Xu, Ge; Fan, Yinzhen; Dong, Xiaomei; Zheng, Lijun; Wang, Bin; Zou, Zhen; Zhang, Jun] Chongqing Med Univ, Inst Life Sci, Mol Biol Lab Resp Dis, Chongqing 400016, Peoples R China; [Du, Hang] Chongqing Prevent & Treatment Ctr Occupat Dis, Chongqing Key Lab Prevent & Treatment Occupat Dis, Chongqing 400060, Peoples R China; [Zhang, Mengling] Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China; [Qin, Xia] Chongqing Med Univ, Affiliated Hosp 1, Dept Pharm, Chongqing 400016, Peoples R China; [Jiang, Xuejun] Chongqing Med Univ, Ctr Expt Teaching Publ Hlth, Expt Teaching & Management Ctr, Chongqing 400016, Peoples R China; [Chen, Chengzhi] Chongqing Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Chongqing 400016, Peoples R China; [Mao, Lejiao; Chen, Chengzhi; Zou, Zhen; Zhang, Jun] Chongqing Med Univ, Res Ctr Environm & Human Hlth, Sch Publ Hlth, Chongqing 400016, Peoples R China"

通信作者："Zou, Z; Zhang, J (通讯作者)，Chongqing Med Univ, Inst Life Sci, Mol Biol Lab Resp Dis, Chongqing 400016, Peoples R China.; Zou, Z; Zhang, J (通讯作者)，Chongqing Med Univ, Res Ctr Environm & Human Hlth, Sch Publ Hlth, Chongqing 400016, Peoples R China."

来源：JOURNAL OF NANOBIOTECHNOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000809569500004

JCR分区：Q1

影响因子：10.2

年份：2022

卷号：20

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：CuONPs; Vascular injury; NRF2; Autophagy; Ubiquitin-proteasome system

摘要："NRF2 is the key antioxidant molecule to maintain redox homeostasis, however the intrinsic mechanisms of NRF2 activation in the context of nanoparticles (NPs) exposure remain unclear. In this study, we revealed that copper oxide NPs (CuONPs) exposure activated NRF2 pathway in vascular endothelial cells. NRF2 knockout remarkably aggravated oxidative stress, which were remarkably mitigated by ROS scavenger. We also demonstrated that KEAP1 (the negative regulator of NRF2) was not primarily involved in NRF2 activation in that KEAP1 knockdown did not significantly affect CuONPs-induced NRF2 activation. Notably, we demonstrated that autophagy promoted N RF2 activation as evidenced by that ATG5 knockout or autophagy inhibitors significantly blocked NRF2 pathway. Mechanically, CuONPs disturbed ubiquitin-proteasome pathway and consequently inhibited the proteasome-dependent degradation of NRF2. However, autophagy deficiency reciprocally promoted proteasome activity, leading to the acceleration of degradation of NRF2 via ubiquitin-proteasome pathway. In addition, the notion that the reciprocal regulation of NRF2 by autophagy and ubiquitin-proteasome was further proven in a CuONPs pulmonary exposure mice model. Together, this study uncovers a novel regulatory mechanism of NRF2 activation by protein degradation machineries in response to CuONPs exposure, which opens a novel intriguing scenario to uncover therapeutic strategies against NPs-induced vascular injury and disease."

基金机构："National Natural Science Foundation of China [81500343, 81903358]; Chongqing Talents: Exceptional Young Talents Project [CQYC2020058650]; Natural Science Foundation of Chongqing [cstc2018jcyjAX0355, cstc2021ycjh-bgzxm0105, cstc2020jcyjmsxmX0155]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJQN201900421, KJQN202000423, KJCXZD2020020, KJQN202100405]; Graduate Research and Innovation Project of Chongqing [CYS21246]; Chongqing Bayu Talented Young Scholar program"

基金资助正文："This work was supported partly by the National Natural Science Foundation of China (81500343 and 81903358), the Chongqing Talents: Exceptional Young Talents Project (CQYC2020058650), the Natural Science Foundation of Chongqing (cstc2018jcyjAX0355, cstc2021ycjh-bgzxm0105 and cstc2020jcyjmsxmX0155), the Science and Technology Research Program of Chongqing Municipal Education Commission (KJQN201900421, KJQN202000423, KJCXZD2020020 and KJQN202100405) and the Graduate Research and Innovation Project of Chongqing (CYS21246). And also supported in part by Chongqing Bayu Talented Young Scholar program for Chengzhi Chen, Zhen Zou and Jun Zhang."