Li Ting, Xu Xuefeng, Zhou Tao, Xie Xuan, Peng Yutao, He Li, He Jin, Luo Wangsheng
Department of Cardiovascular Medicine, The First Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, People's Republic of China.
Department of Cardiovascular Medicine, The First Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, People's Republic of China.
Exp Cell Res. 2025 May 1;448(1):114550. doi: 10.1016/j.yexcr.2025.114550. Epub 2025 Apr 4.
Myocardial ischemia-reperfusion injury (MIRI) is a common complication of cardiovascular disease and its pathogenesis remains unclear. ETS1 (E26 transformation-specific sequence-1) is a transcription factor that plays an important regulatory role in vascular development and generation. Therefore, this study aims to explore the role of ETS1 in MIRI and its potential molecular mechanisms. An OGD/R-induced H9C2 cardiomyocyte model was established, and cell viability was determined by CCK8 and changes in SOD, MDA and GSH levels by ELISA; expression of ETS1, PIM3 and ferroptosis-related indices were determined by immunofluorescence, Western blot and qPCR; at the same time, a mouse MIRI model was established to assess changes in myocardial injury and changes in ferroptosis after knockdown of ETS1. In the OGD/R-induced H9C2 cell model, cell viability was significantly lower than that of the control group, and the level of intracellular ferroptosis was significantly enhanced. Further research has revealed that in the OGD/R-induced H9C2 model, the expression of ETS1 is significantly upregulated. Knockdown of ETS1 can reverse the myocardial cell injury induced by OGD/R. Mechanistically, ETS1 promotes the progression of MIRI by targeting and regulating PIM3, thereby exacerbating ferroptosis. Additionally, in a mouse MIRI model, the knockdown of ETS1 significantly enhances the expression of GPX4, SLC7A11, and FTH1 proteins, inhibits the ferroptosis process, and thereby improves MIRI in mice. The research results indicate that ETS1 promotes the MIRI process through regulating ferroptosis of cardiomyocytes mediated by PIM3. This discovery provides important scientific evidence for further elucidating the mechanisms underlying MIRI and developing therapeutic strategies.
心肌缺血再灌注损伤（MIRI）是心血管疾病的常见并发症，其发病机制尚不清楚。ETS1（E26转化特异性序列-1）是一种转录因子，在血管发育和生成中起重要调节作用。因此，本研究旨在探讨ETS1在MIRI中的作用及其潜在分子机制。建立了氧糖剥夺/复氧（OGD/R）诱导的H9C2心肌细胞模型，通过CCK8检测细胞活力，ELISA检测超氧化物歧化酶（SOD）、丙二醛（MDA）和谷胱甘肽（GSH）水平变化；通过免疫荧光、蛋白质印迹法（Western blot）和实时定量聚合酶链反应（qPCR）检测ETS1、PIM3表达及铁死亡相关指标；同时建立小鼠MIRI模型，评估ETS1基因敲低后心肌损伤变化及铁死亡情况。在OGD/R诱导的H9C2细胞模型中，细胞活力显著低于对照组，细胞内铁死亡水平显著增强。进一步研究发现，在OGD/R诱导的H9C2模型中，ETS1表达显著上调。敲低ETS1可逆转OGD/R诱导的心肌细胞损伤。机制上，ETS1通过靶向调控PIM3促进MIRI进展，从而加剧铁死亡。此外在小鼠MIRI模型中，敲低ETS1可显著增强谷胱甘肽过氧化物酶4（GPX4）、溶质载体家族7成员11（SLC7A11）和铁蛋白重链1（FTH1）蛋白表达，抑制铁死亡过程，从而改善小鼠MIRI。研究结果表明，ETS1通过调节PIM3介导的心肌细胞铁死亡促进MIRI进程。这一发现为进一步阐明MIRI的潜在机制和制定治疗策略提供了重要的科学依据。
