五味子乙素通过抑制Nrf2/GPX4通路介导的铁死亡减轻脓毒症小鼠心肌损伤OA
Mechanistic study of Schisandrin B alleviating myocardial injury in septic mice by inhibiting ferroptosis via activation of the Nrf2/GPX4 axis
目的:探索五味子乙素(Schisandrin B,Sch B)对脓毒症诱导的心肌功能障碍(sepsis-induced myocardial dysfunction,SIMD)的保护作用及其具体的作用机制.方法:将30只雄性C57BL/6J小鼠随机分为对照组(CON组)、脓毒症组(10 mg/kg,LPS组)、LPS+Sch B低剂量(20 mg/kg)组(Sch B-L组)、LPS+Sch B 高剂量(40 mg/kg)组(Sch B-H 组)、LPS+Sch B(40 mg/kg)+Nrf2 抑制剂 ML385(30 mg/kg)组(ML385组),每组各6只,采用LPS腹腔注射构建脓毒症小鼠模型.所有小鼠在造模24 h后进行心脏超声检查,随后对心脏取材并收集相关样本.采用H&E染色评估小鼠心肌组织的病理学组织改变,ELISA检测血清 CK-MB、cTnI、IL-1β、TNF-α的含量,相关试剂盒测定心肌组织 MDA、GSH、SOD、Fe2+水平,免疫组化、Western blot及RT-qPCR检测心肌组织中GPX4、Nrf2、SLC7A11、FTH1、ACSL4的表达情况.结果:与CON组相比,LPS组LVEF、LVFS明显降低,CK-MB、cTnI、IL-1β、TNF-α水平明显增加,H&E染色中可观察到心肌细胞排列紊乱、组织内间隙增宽、水肿以及较多炎性细胞浸润.而给予Sch B预处理的小鼠未见明显的心肌损伤,且心肌组织中MDA、Fe2+水平降低、GSH、SOD水平升高,GPX4、SLC7A11、Nrf2、FTH1蛋白表达以及GPX4、SLC7A11 mRNA含量较LPS组增加,ACSL4水平较LPS组下降.与LPS+Sch B高剂量组相比,Nrf2抑制剂组逆转了Sch B的保护作用,加重心肌细胞损伤及铁死亡程度.结论:五味子乙素通过减轻铁死亡来缓解LPS诱导的脓毒症小鼠心肌功能障碍,其机制可能与Nrf2/GPX4通路的激活相关.
Objective:To explore the protective effect of Schisandrin B(Sch B)on sepsis-induced myocardial dysfunction(SIMD)and its specific mechanism of action.Methods:A total of thirty male C57BL/6J mice were randomly divided into the con-trol group(CON group),the Sepsis group(10 mg/kg LPS group),the LPS+Sch B with low-dose administration(20 mg/kg)group(Sch B-L group),the LPS+Sch B with high-dose administration(40 mg/kg)group(Sch B-H group)and the LPS+Sch B(40 mg/kg)+Nrf2 inhibitor ML385(30 mg/kg)group(ML385 group),with 6 mice in each group,and were treated by intraperi-toneal injection of LPS to construct the sepsis mouse model.All mice underwent cardiac ultrasonography 24 h after modelling,fol-lowed by heart sampling and collection of relevant samples.H&E staining was used to evaluate the pathological tissue changes in myocardial tissues of mice,ELISA was used to detect the levels of serum CK-MB,cTnI,IL-1β,and TNF-α;and relevant kits were used to determine the levels of MDA,GSH,SOD,and Fe2+in myocardial tissues;and immunohistochemistry,Western blotting,and RT-qPCR were used to detect the expression of GPX4,Nrf2,SLC7A11,FTH1,ACSL4 in tissues.Results:Compared to the CON group,LVEF and LVFS in the LPS group were significantly lower,the levels of CK-MB,cTnI,IL-1β,and TNF-α were significantly increased;and disturbed arrangement of cardiomyocytes,widening of intra-tissue gaps,oedema,and a higher inflammatory cell infiltration could be observed in H&E staining.In contrast,mice pretreated with Sch B did not show obvious myocardial injury,and the levels of MDA and Fe2+in myocardial tissues were reduced,the levels of GSH and SOD were increased,the protein expression of GPX4,SLC7A11,Nrf2 and FTH1,and the mRNA content of GPX4 and SLC7A11 were in-creased,and the level of ACSL4 was decreased compared to that of the LPS group.The Nrf2 inhibitor group reversed the protec-tive effect of Schisandra chinensis ethanol and aggravated the degree of cardiomyocyte injury and ferroptosis compared to the Chi-nese medicine group.Conclusion:Schisandrin B alleviated LPS-induced myocardial dysfunction in mice by attenuating ferropto-sis,and its mechanism may be related to the activation of Nrf2/GPX4 pathway.
王磬妍;孙凤霄;张敬;董波
广州中医药大学第一临床医学院,广东 广州 510405山东中医药大学第一临床医学院,山东 济南 250014山东中医药大学第一临床医学院,山东 济南 250014山东第一医科大学附属山东省立医院心内科,山东 济南 250021
医药卫生
五味子乙素脓毒症心肌损伤铁死亡核因子E2相关因子2(Nrf2)谷胱甘肽过氧化酶4(GPX4)
Schisandrin BSepsis-induced myocardial injuryFerroptosisNuclear factor E2 related factor 2(Nrf2)Gluta-thione peroxidase 4(GPX4)
《海南医科大学学报》 2026 (9)
687-696,10
This study was supported by the National Natural Science Foundation of China(82070382)Shandong Province Taishan Scholar Fund(ts20190979) 国家自然科学基金(82070382)山东省泰山学者基金(ts20190979)
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