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

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-09-03 DOI:10.1111/bph.17311
Yun Zhao, Guobin Zheng, Shu Yang, Shangjing Liu, Yifan Wu, Yaodong Miao, Zhen Liang, Yunqing Hua, Jing Zhang, Jia Shi, Dan Li, Yanfei Cheng, Yunsha Zhang, Yuanli Chen, Guanwei Fan, Chuanrui Ma
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Abstract

Background and purpose

Atherosclerosis 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 approach

The 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 results

PNS 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 implications

PNS 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.

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植物提取物PNS通过减少USP2介导的Keap1去泛素化,促进Nrf2介导的铁变态反应抑制,从而减轻动脉粥样硬化。
背景和目的:动脉粥样硬化是心血管疾病的基础。铁变态反应是一种以脂质过氧化为特征的程序性细胞死亡,它是动脉粥样硬化的诱因。植物提取物 PNS(三七皂苷)含有三七的主要活性成分,具有抗动脉粥样硬化的特性。在此,我们确定了三七皂苷及其主要成分是否能通过抑制铁变态反应来减轻动脉粥样硬化,并揭示了其潜在机制:实验方法:在载脂蛋白E-/-小鼠体内测定PNS的抗动脉粥样硬化作用及其与抑制铁蛋白沉积的关系。实验方法:在载脂蛋白E-/-小鼠体内测定 PNS 的抗动脉粥样硬化作用及其与抑制铁蛋白沉积的关系。评估了 USP2-/-巨噬细胞中铁败标志物的表达和 Keap1 的泛素化。最后,通过使用高脂饮食(HFD)和AAV-PCSK9处理USP2-/-小鼠,确定了USP2基因敲除的抗动脉粥样硬化作用:PNS抑制了体内的铁蛋白沉积和动脉粥样硬化。PNS 在体外抑制了铁蛋白沉积和铁蛋白沉积加重的泡沫细胞形成和炎症。从机理上讲,PNS 及其成分通过拮抗 Keap1 激活了 Nrf2,这归因于对 USP2 表达的抑制。USP2 基因敲除可拮抗铁蛋白沉积和铁蛋白沉积加重的泡沫细胞形成和炎症,从而减轻动脉粥样硬化。USP2 基因敲除消除了 PNS 对体外泡沫细胞形成和炎症的抑制作用:PNS减少了USP2介导的Keap1去泛素化,促进了Keap1降解,从而激活了Nrf2,改善了铁代谢,减少了脂质过氧化,从而有助于抗动脉粥样硬化。我们的研究揭示了 PNS 抑制铁代谢和动脉粥样硬化的机制。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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