{"title":"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。","authors":"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","doi":"10.1111/bph.17311","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Background and purpose</h3>\n \n <p>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 (<i>Panax notoginseng saponins</i>), containing the main active ingredients of <i>Panax notoginseng</i>, 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).</p>\n </section>\n \n <section>\n \n <h3> Experimental approach</h3>\n \n <p>The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE<sup>−/−</sup> 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<sup>−/−</sup> macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2<sup>−/−</sup> mice treated with high-fat diet (HFD) and AAV-PCSK9.</p>\n </section>\n \n <section>\n \n <h3> Key results</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Conclusion and implications</h3>\n \n <p>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.</p>\n </section>\n </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4822-4844"},"PeriodicalIF":6.8000,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination\",\"authors\":\"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\",\"doi\":\"10.1111/bph.17311\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Background and purpose</h3>\\n \\n <p>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 (<i>Panax notoginseng saponins</i>), containing the main active ingredients of <i>Panax notoginseng</i>, 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).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Experimental approach</h3>\\n \\n <p>The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE<sup>−/−</sup> 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<sup>−/−</sup> macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2<sup>−/−</sup> mice treated with high-fat diet (HFD) and AAV-PCSK9.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Key results</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion and implications</h3>\\n \\n <p>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.</p>\\n </section>\\n </div>\",\"PeriodicalId\":9262,\"journal\":{\"name\":\"British Journal of Pharmacology\",\"volume\":\"181 23\",\"pages\":\"4822-4844\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-09-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"British Journal of Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/bph.17311\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"British Journal of Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bph.17311","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination
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.
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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