目的 探究三七皂苷R₁对高脂诱发的载脂蛋白E基因敲除（ApoE^-/-）小鼠动脉粥样硬化（atherosclerosis，AS）的治疗作用及机制。方法 高脂喂养雄性ApoE^-/-小鼠12周建立AS模型，将其随机分为模型组及三七皂苷R₁低、高剂量（25、35 mg/kg）组和铁死亡抑制剂Ferrostatin-1（Fer-1，1 mg/kg）组。以相同周龄的雄性C57BL/6J小鼠作为对照组，给予普通饲料饲养。给药5周后采用全自动生化分析仪检测血清总胆固醇（total cholesterol，TC）、三酰甘油（triglycerides，TG）、低密度脂蛋白胆固醇（low density lipoprotein cholesterol，LDL-C）和高密度脂蛋白胆固醇（high density lipoprotein cholesterol，HDL-C）水平；苏木素-伊红（HE）染色和油红O染色观察主动脉粥样斑块程度；加强普鲁士蓝染色法评估斑块铁沉积；生化试剂盒检测主动脉超氧化物歧化酶（superoxide dismutase，SOD）活力及谷胱甘肽（glutathione，GSH）、丙二醛（malondialdehyde，MDA）水平；免疫组化法检测主动脉4-羟基壬烯醛（4-hydroxynonenal，4-HNE）表达；Western blotting检测主动脉核因子E2相关因子2（nuclear factor-erythroid 2-related factor 2，Nrf2）、溶质载体家族7成员11（solute carrier family 7 member 11，SLC7A11）、谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4）及4-HNE蛋白表达；qRT-PCR法检测主动脉Nrf2、Gpx4、前列腺素内过氧化物合酶2（prostaglandin-endoperoxide synthase 2，Ptgs2）mRNA表达。结果 三七皂苷R₁低、高剂量组及Fer-1组不同程度地影响ApoE^-/-小鼠的血脂水平（P＜0.05、0.01），明显减轻主动脉粥样斑块程度，抑制铁沉积（P＜0.01），提高SOD、GSH抗氧化能力（P＜0.05、0.01），减少脂质过氧化MDA水平和4-HNE蛋白表达（P＜0.05、0.01），上调铁死亡相关核Nrf2、SLC7A11、GPX4蛋白及Nrf2、Gpx4 mRNA的表达（P＜0.01），下调Ptgs2 mRNA的表达（P＜0.01），以三七皂苷R₁高剂量组效果最为显著。结论 三七皂苷R₁改善ApoE^-/-小鼠脂代谢紊乱，抑制动脉粥样斑块形成，具有抗AS的作用，其机制可能与减少斑块铁沉积、激活Nrf2/SLC7A11/GPX4通路减少脂质过氧化，抑制铁死亡有关。

Objective To explore the therapeutic effect and mechanism of notoginsenoside R₁ (NGR1) on ApoE^-/- mice with high fat diet induced atherosclerosis (AS). Methods Male ApoE^-/-mice were fed high-fat diet for 12 weeks to establish atherosclerotic model, then mice were randomly divided into model group, NGR1 low-and high dose (25, 35 mg/kg) groups, Ferrostatin-1 (Fer-1, 1 mg/kg) group. Male C57BL/6J mice of the same week age were used as control group and were fed on a general diet. After five weeks of feeding, the levels of total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were measured by automatic biochemical analyzer; Hematoxylin-eosin (HE) and oil red O staining were used to observe the degree of aortic atherosclerotic plaque; Enhanced Prussian blue staining was used for the assessment of iron deposits in aortic plaques; The activity of super oxide dismutase (SOD) and levels of glutathione (GSH), malondialdehyde (MDA) in aortic tissues were determined by biochemical assay; The expression of 4-hydroxynonenal (4-HNE) protein in aorta was detected by immunohistochemistry; Western blotting was performed to determine the protein expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4) and 4-HNE in aortic plaques; qRT-PCR was performed to measure the mRNA expressions of Nrf2, Gpx4 and prostaglandin-endoperoxide synthase 2 (Ptgs2). Results The blood lipid level of ApoE^-/- mice was affected to different degrees (P < 0.05, 0.01), the degree of atherosclerosis plaque in aortic plaques was significantly reduced, iron deposition was inhibited (P < 0.01), the antioxidant capacities of SOD and GSH were improved (P < 0.05, 0.01), the level of lipid peroxidation MDA content and 4-HNE protein expression were reduced (P < 0.05, 0.01), the expressions of nuclear Nrf2, SLC7A11, GPX4 protein and Nrf2, Gpx4 mRNA associated with ferroptosis were increased (P < 0.01), the expression of Ptgs2 mRNA was reduced (P < 0.01) in NGR1 low- and high-dose groups and Fer-1 group. NGR1 high-dose group had more significant improvement effect on the above indexes. Conclusion NGR1 can improve lipid metabolism disorder in ApoE^-/- mice, reduce atherosclerotic plaque formation in ApoE^-/- mice, and has antiatherogenic effect. Its mechanism may be related to reducing iron deposition, activating Nrf2/SLC7A11/GPX4 pathway to reduce lipid peroxidation and inhibit ferroptosis.

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国家自然科学基金资助项目（82104704）；湖北省教育厅科学研究计划项目重点项目（D2022006）；武汉市卫健委青年项目（WZ20Y07）；武汉市卫健委中医药科研面上项目（WZ22C55）