Fang Jingyun, Zhou Yuming
Department of Emergency, Ganzhou People's Hospital Ganzhou 341000, Jiangxi, China.
Am J Transl Res. 2023 Feb 15;15(2):1017-1025. eCollection 2023.
This study aimed to investigate the mechanism of γ-secretase inhibitor (GSI) in myocardial repair in septic rats.
Thirty-six healthy male Wistar rats were randomly and equally divided into control groups, model group and intervention group. The model group and the intervention group were treated with ligation of cecum and perforation to build sepsis model, and the intervention group received intraperitoneal injection of GSI II (DAPT). Serum levels of Troponin T (cTnT), creatine kinase isoenzyme (CK-MB) and interleukin-17 were measured by ELISA. The Th17 cell percentage in peripheral blood mononuclear cells in CD4 cells was determined by flow cytometry, and myocardial tissue cells in each group were measured by TUNEL. The mRNA of RORγt was measured by real-time quantitative PCR, and the protein expressions of Notch1, Hes1 and HIF-α in myocardial tissue were measured by Western blot.
The cTnT, CK-MB, Th17 and Th17/CD4 levels in the model group and the intervention group were remarkably higher than those in the control group (), while those in the intervention group were remarkably lower than those in the model group (). Myocardial apoptosis rate, myocardial RORγt mRNA and protein expressions of Notch1, Hes1 and HIF-α in the model group and the intervention group were obviously higher than those in control group (), and those in the intervention group were obvious lower than those in the model group ().
γ secretase inhibitors have clearly protective effects on cardiomyocytes, and the mechanism may be associated with Notch blocking and RORγt expression, which inhibit immune damage induced by abnormal activation of Th17.
本研究旨在探讨γ-分泌酶抑制剂（GSI）在脓毒症大鼠心肌修复中的作用机制。
将36只健康雄性Wistar大鼠随机等分为对照组、模型组和干预组。模型组和干预组采用结扎盲肠并穿孔的方法建立脓毒症模型，干预组腹腔注射GSI II（DAPT）。采用酶联免疫吸附测定法（ELISA）检测血清肌钙蛋白T（cTnT）、肌酸激酶同工酶（CK-MB）和白细胞介素-17水平。采用流式细胞术检测CD4细胞中外周血单个核细胞的Th17细胞百分比，采用TUNEL法检测各组心肌组织细胞凋亡情况。采用实时定量聚合酶链反应（PCR）检测RORγt的mRNA水平，采用蛋白质免疫印迹法（Western blot）检测心肌组织中Notch1、Hes1和低氧诱导因子-α（HIF-α）的蛋白表达。
模型组和干预组的cTnT、CK-MB、Th17及Th17/CD4水平均显著高于对照组（），而干预组显著低于模型组（）。模型组和干预组的心肌凋亡率、心肌RORγt mRNA水平及Notch1、Hes1和HIF-α蛋白表达均明显高于对照组（），而干预组明显低于模型组（）。
γ-分泌酶抑制剂对心肌细胞具有明显的保护作用，其机制可能与阻断Notch信号及RORγt表达有关，从而抑制Th17异常激活所致的免疫损伤。
