First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
Br J Pharmacol. 2024 Dec;181(23):4822-4844. doi: 10.1111/bph.17311. Epub 2024 Sep 3.
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).
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.
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.
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.
动脉粥样硬化是心血管疾病的基础。铁死亡是一种以脂质过氧化为特征的程序性细胞死亡形式，它有助于动脉粥样硬化的发生。植物提取物 PNS（三七总皂苷）含有三七的主要活性成分，具有抗动脉粥样硬化作用。在此，我们确定 PNS 及其主要成分是否可以通过抑制铁死亡来减轻动脉粥样硬化，并揭示了潜在的机制。
在载脂蛋白 E 小鼠中确定 PNS 的抗动脉粥样硬化作用及其与抑制铁死亡的关系。在体外，在存在铁死亡诱导剂的情况下，研究了 PNS 成分的抗铁死亡作用及其机制。评估了 USP2 巨噬细胞中铁死亡标志物的表达和 Keap1 的泛素化。最后，通过使用高脂饮食（HFD）和 AAV-PCSK9 处理的 USP2 敲除小鼠来确定 USP2 敲除的抗动脉粥样硬化作用。
PNS 抑制体内铁死亡和动脉粥样硬化。PNS 抑制铁死亡和铁死亡加重的泡沫细胞形成和炎症反应。在机制上，PNS 和其成分通过拮抗 Keap1 激活 Nrf2，这归因于抑制 USP2 的表达。USP2 敲除拮抗铁死亡和铁死亡加重的泡沫细胞形成和炎症反应，从而减轻动脉粥样硬化。USP2 敲除消除了 PNS 在体外对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，并促进了 Keap1 的降解，从而激活了 Nrf2，改善了铁代谢并减少了脂质过氧化，从而导致了抗动脉粥样硬化的结果。我们的研究揭示了 PNS 抑制铁死亡和动脉粥样硬化的机制。
