北京中医药大学学报2024，Vol.47Issue(3)：383-393,11.DOI:10.3969/j.issn.1006-2157.2024.03.013
血管软化丸调控Nrf2/xCT/GPX4通路抑制血管内皮细胞铁死亡改善动脉粥样硬化的作用机制
Xueguan Ruanhua Pills improve atherosclerosis by inhibiting ferroptosis through the Nrf2/xCT/GPX4 pathway
摘要
Abstract
Objective We investigated the effects of Xueguan Ruanhua Pills(XGRHW) on ferroptosis in ApoE-/- atherosclerotic mice through the nuclear factor E2 related factor 2 (Nrf2)/xCT/glutathione peroxidase 4 (GPX4) signaling pathway.Methods Ten male C57BL/6J mice in the normal group were fed normal chow. Additionally, 50 ApoE-/- mice were fed high-fat chow for 12 weeks, and were divided into the following five groups (10 mice per group): the model group, the XGRHW low-dose (2.34g/kg) group, the XGRHW high-dose (4.68 g/kg) group, the XGRHW high-dose combined with the Nrf2 inhibitor ML385 (0.03 g/kg) group, and the ferrostatin-1 (1 mg/kg) group. Drugs were administered for 6 weeks. The blood levels of four types of lipids were detected by an automatic lipid analyzer, lipid deposition in the aorta was observed by Oil Red O staining, histomorphological changes in the aortic sinus were observed by HE staining, the serum levels of Fe2+, MDA, GSH, and SOD were determined by colorimetric assays, and the expression levels of FTH1 and FTL in the aortic sinus were observed by immunofluorescence. The protein levels of Nrf2, xCT, and GPX4 in mouse aortic tissues were detected by Western blotting. The ultrastructural changes of aortic mitochondria were observed by transmission electron microscopy.Results Compared with the normal group, mice in the model group showed obvious lipid plaque deposition in the aorta, severely calcified lesions in the aortic sinus, elevated serum levels of TC, TG, LDL-C, Fe2+, and MDA, decreased levels of HDL-C, SOD, and GSH (P<0.01), and decreased protein expressions of aortic Nrf2, xCT, and GPX4 as well as the iron storage proteins FTH1 and FTL (P<0.01), and serve damage to mitochondrial structure and morphology. Compared with the model group, the relative aortic plaque area was decreased, calcified lesions in the aortic sinus were decreased, serum levels of TC, TG, LDL-C, Fe2+, and MDA were decreased, and HDL-C, SOD, and GSH levels were increased in the XGRHW low-dose and high-dose and ferrostatin-1 groups (P<0.05 or P<0.01), and Nrf2, xCT, GPX4, and the iron storage proteins FTH1 and FTL were upregulated in aortic tissues (P<0.05 or P<0.01), and mitochondrial structure approaching normal. In the XGRHW high-dose+ML385 group, compared with the XGRHW high-dose group, the levels of blood lipids and lipid peroxidation were increased and the protein levels of Nrf2, xCT, and GPX4 in aortic tissue and the iron storage proteins FTH1 and FTL were decreased (P<0.01), and mitochondrial structure was damaged indicating that ML385 could inhibit the therapeutic effect of the XGRHW in atherosclerotic mice.Conclusion The XGRHW can improve blood lipid levels and reduce the degree of arterial plaque lesions in atherosclerotic mice, and its mechanism of action may be related to activation of the Nrf2/xCT/GPX4 pathway to inhibit ferroptosis.关键词
动脉粥样硬化/血管软化丸/核因子E2相关因子2/胱氨酸谷氨酸反向转运蛋白/谷胱甘肽过氧化物酶4通路/铁死亡/脂质过氧化/小鼠Key words
atherosclerosis/Xueguan Ruanhua Pills/nuclear factor E2 related factor 2/xCT/glutathione peroxidase 4 pathway/ferroptosis/lipid peroxidation/mice分类
医药卫生引用本文复制引用
孙孟艳,秦合伟,李彦杰,王梦楠,刘丹丹,高洋..血管软化丸调控Nrf2/xCT/GPX4通路抑制血管内皮细胞铁死亡改善动脉粥样硬化的作用机制[J].北京中医药大学学报,2024,47(3):383-393,11.基金项目
国家自然科学基金面上项目(No.82374551) （No.82374551）
中原英才计划中原青年拔尖人才项目(豫组通[2021]No.44) （豫组通[2021]No.44）
河南省中医药拔尖人才培养项目(豫卫中医函[2021]No.15) （豫卫中医函[2021]No.15）
河南中医药大学研究生科研创新能力提升计划项目(No.2022KYCX074,No.2022KYCX075) National Natural Science Foundation of China(No.82374551) （No.2022KYCX074,No.2022KYCX075）
