人参总皂苷调控SLC7A11/GPX4介导的铁死亡减轻脓毒症模型大鼠心肌损伤的机制研究

Mechanism of total ginsenosides in alleviating myocardial injury in septic rat models by regulating SLC7A11/GPX4-mediated ferroptosis

  • 摘要:
    目的  探讨人参总皂苷(TG)调控溶质载体家族7成员11/谷胱甘肽过氧化物酶4(SLC7A11/GPX4)介导的铁死亡减轻脓毒症模型大鼠心肌损伤的机制。
    方法  将90只SPF级雄性大鼠随机分为Sham组(假手术组)、脓毒症心肌病(SCM)组、TG40组(SCM模型大鼠灌胃40 mg/kg的TG)、TG160组(SCM模型大鼠灌胃160 mg/kg的TG)、TG160+RSL3组(SCM模型大鼠灌胃160 mg/kg的TG并腹腔注射10 mg/kg的铁死亡诱导剂RSL3)。采用盲肠结扎穿孔法构建SCM模型; 测定各组大鼠心功能; 苏木精-伊红(HE)染色观察心肌组织的病理学形态变化; 采用酶联免疫吸附测定法检测肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-6、肌酸激酶同工酶(CK-MB)、肌红蛋白(Mb)、肌钙蛋白I(cTnI)水平; 采用蛋白免疫印迹检测有丝分裂氧化酶(NOX)1、NOX2、NOX4、SLC7A11、GPX4表达水平; 测定心肌组织中Fe2+以及总铁离子的水平。
    结果  与Sham组相比, SCM组左心室射血分数(LVEF)、左心室短轴缩短率(LVFS)和SLC7A11、GPX4蛋白表达水平降低, CK-MB、Mb、cTnI、TNF-α、IL-β、IL-6、Fe2+和总铁离子水平、NOX1、NOX2和NOX4蛋白表达水平增加; 与SCM组相比, TG40组、TG160组LVEF、LVFS和SLC7A11、GPX4蛋白表达水平增加, CK-MB、Mb、cTnI、TNF-α、IL-β、IL-6、Fe2+和总铁离子水平、NOX1、NOX2和NOX4蛋白表达水平呈剂量依赖性降低; 与TG160组相比, TG160+RSL3组LVEF、LVFS和SLC7A11、GPX4蛋白表达水平降低, CK-MB、Mb、cTnI、TNF-α、IL-β、IL-6、Fe2+和总铁离子水平、NOX1、NOX2和NOX4蛋白表达水平增加; 上述组间差异均有统计学意义(P<0.05)。
    结论  TG能显著抑制脓毒症诱导的心肌组织炎症和氧化应激反应,改善心功能,减轻心肌组织损伤,其机制可能是通过激活SLC7A11/GPX4信号通路来抑制铁死亡实现的。

     

    Abstract:
    Objective  To investigate the mechanism of total ginsenosides(TG) in alleviating myocardial injury in septic rat models by regulating solute carrier family 7 member 11/glutathione peroxidase 4 (SLC7A11/GPX4)-mediated ferroptosis.
    Methods  Ninety SPF-grade male rats were randomly divided into five groups: Sham group(sham operation), septic cardiomyopathy (SCM) group, TG40 group (SCM model rats gavaged with 40 mg/kg TG), TG160 group (SCM model rats gavaged with 160 mg/kg TG), and TG160+RSL3 group (SCM model rats gavaged with 160 mg/kg TG and intraperitoneally injected with 10 mg/kg ferroptosis inducer RSL3). The SCM model was established using the cecal ligation and puncture method. Cardiac function was assessed in each group. Hematoxylin-eosin (HE) staining was performed to observe pathological changes in myocardial tissue. Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, creatine kinase-MB (CK-MB), myoglobin (Mb), and cardiac troponin I (cTnI) were measured by enzyme-linked immunosorbent assay. Protein expression levels of NADPH oxidase (NOX)1, NOX2, NOX4, SLC7A11, and GPX4 were detected by western blotting. Levels of Fe2+ and total iron in myocardial tissue were also determined.
    Results  Compared with the Sham group, the SCM group exhibited decreased left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and protein expression of SLC7A11 and GPX4, along with increased levels of CK-MB, Mb, cTnI, TNF-α, IL-1β, IL-6, Fe2+, total iron, and protein expression of NOX1, NOX2, and NOX4 (P < 0.05). Compared with the SCM group, the TG40 and TG160 groups showed dose-dependent increases in LVEF, LVFS, and SLC7A11/GPX4 expression, as well as reductions in CK-MB, Mb, cTnI, TNF-α, IL-1β, IL-6, Fe, total iron, and NOX1/NOX2/NOX4 expression (P < 0.05). In contrast, the TG160+RSL3 group displayed lower LVEF, LVFS, and SLC7A11/GPX4 expression, and higher levels of the aforementioned biomarkers compared with the TG160 group (P < 0.05).
    Conclusion  TG significantly suppresses sepsis-induced myocardial inflammation and oxidative stress, improves cardiac function, and mitigates myocardial injury, likely by inhibiting ferroptosis via activation of the SLC7A11/GPX4 signaling pathway.

     

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