2025年7月14日 周一
首页 > 按月查看>2023年第3月 >231-237. DOI:10.20039/j.cnki.10073949.2023.03.008
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银杏素通过激活Nrf2/SLC7A11/GPX4信号通路抑制ox-LDL诱导的血管内皮细胞铁死亡
作者:
作者单位:

(西安高新医院心血管内科一病区,陕西省西安市 710000)

作者简介:

韩震海,主治医师,研究方向为心内科相关疾病诊断与治疗,E-mail:Hanzh1222@163.com。通信作者潘立栋,主治医师,研究方向为心内科相关疾病诊断与治疗,E-mail:865269093@qq.com。

基金项目:

西安市科技计划项目(20YXJ003(2))


Influences of ginkgetin on ox-LDL-induced ferroptosis in vascular endothelial cells by regulating Nrf2/SLC7A11/GPX4 signaling pathway
Author:
Affiliation:

The First Ward, Department of Cardiovascular Medicine, Xi'an Gaoxin Hospital, Xi'an, Shaanxi 710000, China)

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    摘要:

    目的]探讨银杏素调节核因子E2相关因子2(Nrf2)/溶质载体家族7成员11(SLC7A11)/谷胱甘肽过氧化物酶4(GPX4)信号通路对氧化型低密度脂蛋白(ox-LDL)诱导的血管内皮细胞铁死亡的影响。 [方法]将人脐静脉内皮细胞EA.hy926分为正常对照组(正常培养)、ox-LDL组(50 mg/L ox-LDL)、银杏素低剂量组(50 mg/L ox-LDL＋10 μmol/L银杏素)、银杏素中剂量组(50 mg/L ox-LDL＋20 μmol/L银杏素)、银杏素高剂量组(50 mg/L ox-LDL＋40 μmol/L银杏素)、ML385组(50 mg/L ox-LDL＋40 μmol/L银杏素+1 μmol/L的Nrf2抑制剂ML385)、Erastin组(50 mg/L ox-LDL＋40 μmol/L银杏素+5 μmol/L的SLC7A11抑制剂Erastin)、RSL3组(50 mg/L ox-LDL＋40 μmol/L银杏素+0.5 μmol/L的GPX4抑制剂RSL3)；MTT法检测细胞存活率；试剂盒检测细胞超氧化物歧化酶(SOD)、丙二醛(MDA)、还原型谷胱甘肽(GSH)水平；特异性荧光探针法检测细胞内铁含量；DCFH-DA荧光探针法和氟硼二吡咯(BODIPYTM)法检测细胞内活性氧(ROS)和脂质ROS水平；Western blot检测细胞Nrf2、SLC7A11、GPX4、4-羟基壬烯酸(4-HNE)、环氧合酶2(COX2)、p53蛋白表达。 [结果]与正常对照组相比,ox-LDL组细胞存活率、SOD含量、GSH含量以及Nrf2、SLC7A11、GPX4表达明显降低(P＜0.05),MDA含量、细胞内Fe2＋含量、细胞内ROS、脂质ROS以及4-HNE、COX2、p53表达显著升高(P＜0.05)。与ox-LDL组相比,银杏素低、中、高剂量组细胞存活率、SOD含量、GSH含量及Nrf2、SLC7A11、GPX4表达明显升高(P＜0.05),MDA含量、Fe2＋含量、细胞内ROS、脂质ROS及4-HNE、COX2、p53表达显著降低(P＜0.05)。与银杏素高剂量组相比,ML385组、Erastin组、RSL3组均减弱了银杏素对ox-LDL诱导的血管内皮细胞铁死亡的抑制作用。 [结论]银杏素通过激活Nrf2/SLC7A11/GPX4通路抑制ox-LDL诱导的血管内皮细胞铁死亡。

    Abstract:

    Aim To investigate the influences of ginkgetin on the ferroptosis of vascular endothelial cells induced by oxidized low density lipoprotein (ox-LDL) by regulating the nuclear factor erythroid-2 related factor 2 (Nrf2)/solute carrier protein 7 family member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway. Methods Human umbilical vein cell fusion cells EA.hy926 were grouped into normal control group (normal culture), ox-LDL group (50 mg/L ox-LDL), and ginkgetin low dose group (50 mg/L ox-LDL+10 μmol/L ginkgetin), middle dose group (50 mg/L ox-LDL+20 μmol/L ginkgetin), high dose group (50 mg/L ox-LDL+40 μmol/L ginkgetin), ML385 group (50 mg/L ox-LDL+40 μmol/L ginkgetin+1 μmol/L Nrf2 inhibitor ML385), Erastin group (50 mg/L ox-LDL+40 μmol/L ginkgetin+5 μmol/L SLC7A11 inhibitor Erastin), RSL3 group (50 mg/L ox-LDL+40 μmol/L ginkgetin+0.5 μmol/L GPX4 inhibitor RSL3). Cell viability was detected by tetramethylazolium salt (MTT) method. The kits were applied to detect the levels of cellular superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH). The intracellular iron content was detected by specific fluorescent probe method. The levels of intracellular reactive oxygen species (ROS) and lipid ROS were detected by 2′, 7′-dichlorofluorescein diacetate (DCFH-DA) fluorescent probe method and boron dipyrrole (BODIPYTM) method; Western blot was applied to detect the protein expressions of cellular Nrf2, SLC7A11, GPX4,4-hydroxynonenoic acid (4-HNE), cyclooxygenase 2 (COX2), and p53. Results Compared with the normal control group, the cell viability, SOD content, GSH content, expressions of Nrf2, SLC7A11 and GPX4 were obviously decreased in the ox-LDL group (P＜0.05); the MDA content, Fe2＋ content, ROS, lipid ROS, expressions of 4-HNE, COX2, p53 were obviously increased (P＜0.05). Compared with the ox-LDL group, the cell viability, SOD content, GSH content, expressions of Nrf2, SLC7A11 and GPX4 were obviously increased in low, middle and high dose groups of ginkgetin (P＜0.05); the MDA content, Fe2＋ content, ROS, lipid ROS, expressions of 4-HNE, COX2, p53 were obviously decreased (P＜0.05). Compared with the high dose ginkgetin group, the ML385 group, Erastin group and RSL3 group attenuated the inhibitory effect of ginkgetin on ox-LDL-induced vascular endothelial cell ferroptosis. Conclusion Ginkgetin inhibits ox-LDL-induced vascular endothelial cell ferroptosis by activating the Nrf2/SLC7A11/GPX4 pathway.

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韩震海,王飞飞,潘立栋.银杏素通过激活Nrf2/SLC7A11/GPX4信号通路抑制ox-LDL诱导的血管内皮细胞铁死亡[J].中国动脉硬化杂志,2023,31(3):231~237.

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  • 收稿日期:2022-08-11
  • 最后修改日期:2022-12-30
  • 在线发布日期: 2023-03-24

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