The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination

Zhao, Yun1; Zheng, Guobin2; Yang, Shu3; Liu, Shangjing1; Wu, Yifan1; Miao, Yaodong4; Liang, Zhen3; Hua, Yunqing1; Zhang, Jing1; Shi, Jia1; Li, Dan1; Cheng, Yanfei1; Zhang, Yunsha1; Chen, Yuanli5; Fan, Guanwei1; Ma, Chuanrui1

2024-09-01

10.1111/bph.17311

BRITISH JOURNAL OF PHARMACOLOGY   影响因子和分区

0007-1188

1476-5381

["Background and purposeAtherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (Panax notoginseng saponins), containing the main active ingredients of Panax notoginseng, exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s).Experimental approachThe anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE-/- mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2-/- macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2-/- mice treated with high-fat diet (HFD) and AAV-PCSK9.Key resultsPNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro.Conclusion and implicationsPNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS.","image"]

atherosclerosis deubiquitination ferroptosis Nrf2 PNS USP2

SCI

英语

其他

National Natural Science Foundation of China["82373867","82370876","82000824","82003747"] ; Second batch of high-level talents in the health industry selection and training project[TJSQNYXXR-D2-064] ; Natural Science Foundation of Tianjin[20JCZXJC00150] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine["ZYYCXTD-C-202203","ZYYCXTD-D-202207"] ; Tianjin College Students Innovation and Entrepreneurship Training Program[202210063008] ; Science & Technology Development Fund of Tianjin Education Commission for Higher Education["2021KJ151","2023ZD034"] ; Tianjin Administration of Traditional Chinese Medicine Research topic on the integration of traditional Chinese medicine and Western medicine[2021102]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:001303619800001

WILEY

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Tianjin Univ Tradit Chinese Med, Teaching Hosp 1, Natl Clin Res Ctr Chinese Med Acupuncture & Moxibu, 88 Chang Ling Rd, Tianjin, Peoples R China
2.Tianjin Med Univ, Chu Hsien I Mem Hosp & Tianjin Inst Endocrinol, Tianjin Key Lab Metab Dis, NHC Key Lab Hormones & Dev, Tianjin, Peoples R China
3.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen Peoples Hosp, Dept Geriatr, Shenzhen, Peoples R China
4.Tianjin Univ Tradit Chinese Med, Affiliated Hosp 2, Tianjin, Peoples R China
5.Hefei Univ Technol, Sch Food & Biol Engn, Nutr Regulat Anhui Dept Educ, Key Lab Major Metab Dis, Hefei, Peoples R China

Zhao, Yun,Zheng, Guobin,Yang, Shu,et al. The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination[J]. BRITISH JOURNAL OF PHARMACOLOGY,2024.

Zhao, Yun.,Zheng, Guobin.,Yang, Shu.,Liu, Shangjing.,Wu, Yifan.,...&Ma, Chuanrui.(2024).The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination.BRITISH JOURNAL OF PHARMACOLOGY.

Zhao, Yun,et al."The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination".BRITISH JOURNAL OF PHARMACOLOGY (2024).