Chen Jiye, Zhang Xiaonan, Sun Changxin, Wang Zeping, Li Xiaoya, Hu Lanqing, Yuan Yongfang, Wu Min, Liu Longtao
State Key Laboratory of Traditional Chinese Medicine Syndrome/National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, 100091, People's Republic of China.
Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong, 250014, People's Republic of China.
J Inflamm Res. 2025 Sep 2;18:12105-12121. doi: 10.2147/JIR.S530995. eCollection 2025.
Atherosclerosis (AS) is a chronic inflammatory vascular disease in which ferroptosis plays a crucial role. While the combination of polydatin (PD) and Hawthorn leaf flavonoids (HLF), termed PD and HLF combination (PH), is effective against AS, its impact on plaque vulnerability and the underlying mechanisms remain unclear.
ApoE mice were fed a high-fat diet (HFD) for 12 weeks to establish an AS model and treated with PD, HLF and Simvastatin for 8 weeks. Histological characterization of atherosclerotic lesions was performed using pathological staining. Transmission electron microscopy (TEM) was used to evaluate mitochondrial damage. Lipid peroxidation levels were assessed using ELISA. Immunofluorescence staining was performed to verify Nrf2 nuclear translocation. Expression of the Nrf2/HO-1/GPX4 axis was detected using Western blotting and PCR.
HFD significantly promoted AS lesion formation and instability, and caused severe iron overload and lipid peroxidation in atherosclerotic lesions. PH significantly reduced dyslipidemia and suppressed atherosclerotic plaque progression in ApoE-/- mice. Meanwhile, the PH combination visibly reduced iron accumulation and improved mitochondrial ultrastructure. Additionally, PH combination decreased the levels of ROS, MDA, 4HNE, 8-OHdG, and Fe, while increasing GSH levels. Further studies showed that the PH combination enhanced the translocation of Nrf2 into the nucleus, HO-1, GPX4, SLC7A11, FPN1, and FTH1 expression, and inhibited cytoplasmic Nrf2 and TFR1 expression.
PH combination reduced the instability of atherosclerotic lesions in ApoE mice by modulating iron metabolism and lipid peroxidation through activation of the Nrf2/ HO-1/GPX4 axis.
动脉粥样硬化（AS）是一种慢性炎症性血管疾病，铁死亡在其中起关键作用。虽然虎杖苷（PD）与山楂叶黄酮（HLF）的组合，即PD与HLF联合用药（PH）对AS有效，但其对斑块易损性及潜在机制的影响仍不清楚。
给载脂蛋白E基因敲除（ApoE）小鼠喂食高脂饮食（HFD）12周以建立AS模型，并用PD、HLF和辛伐他汀治疗8周。使用病理染色对动脉粥样硬化病变进行组织学特征分析。采用透射电子显微镜（TEM）评估线粒体损伤。使用酶联免疫吸附测定（ELISA）评估脂质过氧化水平。进行免疫荧光染色以验证核因子E2相关因子2（Nrf2）的核转位。使用蛋白质免疫印迹法和聚合酶链反应（PCR）检测Nrf2/血红素加氧酶-1（HO-1）/谷胱甘肽过氧化物酶4（GPX4）轴的表达。
HFD显著促进AS病变形成和不稳定，并导致动脉粥样硬化病变中严重的铁过载和脂质过氧化。PH显著降低血脂异常，并抑制ApoE基因敲除小鼠动脉粥样硬化斑块进展。同时，PH联合用药明显减少铁蓄积并改善线粒体超微结构。此外，PH联合用药降低了活性氧（ROS）、丙二醛（MDA）、4-羟基壬烯醛（4HNE）、8-羟基脱氧鸟苷（8-OHdG）和铁的水平，同时提高了谷胱甘肽（GSH）水平。进一步研究表明，PH联合用药增强了Nrf2向细胞核的转位、HO-1、GPX4、溶质载体家族7成员11（SLC7A11）、铁转运蛋白1（FPN1）和铁蛋白重链1（FTH1）的表达，并抑制细胞质Nrf2和转铁蛋白受体1（TFR1）的表达。
PH联合用药通过激活Nrf2/HO-1/GPX4轴调节铁代谢和脂质过氧化，降低ApoE小鼠动脉粥样硬化病变的不稳定性。
