Huang Y, Zhang G, Liang H, Cao Z, Ye H, Gao Q
Department of Physiology, Bengbu Medical College, Bengbu 233000, China.
Department of Clinical Medicine, Bengbu Medical College, Bengbu 233000, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2022 Feb 20;42(2):256-262. doi: 10.12122/j.issn.1673-4254.2022.02.13.
To explore the contribution of ferroptosis to myocardial injury in mouse models of sepsis and the role lipocalin-2 (Lcn2) in ferroptosis.
Adult male C57BL/6 mice were randomized equally into sham-operated group, cecal ligation and puncture (CLP)-induced sepsis group, and CLP + Fer-1 group where the mice received intraperitoneal injection of 5 mg/mL Fer-1 (5 mg/kg) 1 h before CLP. The left ventricular functions (including LVEF%, LVFS%, LVIDd and LVIDs) of the mice were assessed by echocardiography at 24 h after CLP. Myocardial injury in the mice was observed with HE staining, and the changes of myocardial ultrastructure and mitochondria were observed using transmission electron microscopy (TEM). Serum TNF-α level was measured with ELISA, and the changes of myocardial iron content were detected using tissue iron kit. The protein expressions of myocardial Lcn2, glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) were determined with Western blotting.
The septic mice showed significantly decreased LVEF%, LVFS% and LVIDd and increased LVIDs at 24 h after CLP ( < 0.05), and these changes were significantly improved by Fer-1 treatment. Sepsis caused obvious myocardial pathologies and changes in myocardial ultrastructure and mitochondria, which were significantly improved by Fer-1 treatment. Fer-1 treatment also significantly ameliorated sepsis-induced elevations of serum TNF-α level, myocardial tissue iron content, and Lcn2 protein expression and the reduction of GPX4 and FSP1 protein expression levels ( < 0.05).
GPX4- and FSP1-mediated ferroptosis are involved in myocardial injury in mice with CLP-induced sepsis, and inhibition of ferroptosis can attenuate septic myocardial injury, in which Lcn2 may play a role.
探讨铁死亡在脓毒症小鼠模型心肌损伤中的作用以及脂质运载蛋白2（Lcn2）在铁死亡中的作用。
将成年雄性C57BL/6小鼠随机均分为假手术组、盲肠结扎穿孔（CLP）诱导的脓毒症组和CLP + Fer-1组，CLP + Fer-1组小鼠在CLP前1小时腹腔注射5 mg/mL Fer-1（5 mg/kg）。在CLP后24小时通过超声心动图评估小鼠的左心室功能（包括左心室射血分数%、左心室短轴缩短率%、左心室舒张末期内径和左心室收缩末期内径）。用HE染色观察小鼠心肌损伤情况，用透射电子显微镜（TEM）观察心肌超微结构和线粒体的变化。用ELISA检测血清TNF-α水平，用组织铁试剂盒检测心肌铁含量的变化。用蛋白质免疫印迹法测定心肌Lcn2、谷胱甘肽过氧化物酶4（GPX4）和铁死亡抑制蛋白1（FSP1）的蛋白表达。
脓毒症小鼠在CLP后24小时左心室射血分数%、左心室短轴缩短率%和左心室舒张末期内径显著降低，左心室收缩末期内径增加（P < 0.05），而Fer-1治疗显著改善了这些变化。脓毒症导致明显的心肌病变以及心肌超微结构和线粒体的变化，Fer-1治疗显著改善了这些变化。Fer-1治疗还显著改善了脓毒症诱导的血清TNF-α水平升高、心肌组织铁含量升高、Lcn2蛋白表达升高以及GPX4和FSP1蛋白表达水平降低（P < 0.05）。
GPX4和FSP1介导的铁死亡参与CLP诱导的脓毒症小鼠的心肌损伤，抑制铁死亡可减轻脓毒症心肌损伤，其中Lcn2可能发挥作用。
