Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China.
Department of Cardiovascular Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Biochim Biophys Acta Mol Cell Res. 2024 Oct;1871(7):119804. doi: 10.1016/j.bbamcr.2024.119804. Epub 2024 Jul 29.
Myocardial fibrosis is an important pathological feature of dilated cardiomyopathy (DCM). The roles of SOCS2 in fibrosis of different organs are controversial. Herein, we investigated the function and potential mechanism of SOCS2 in myocardial fibrosis.
Bioinformatics, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), real-time fluorescence quantitative PCR (qPCR), rat primary myocardial fibroblasts (rCFs) culture, doxorubicin (DOX) induced mouse dilated cardiomyopathy (DCM) model, and in vivo adeno-associated virus (AAV) infection were used to explore the role of SOCS2 in DCM.
Bioinformatics analysis showed that SOCS2 was positively correlated with fibrosis related factors. SOCS2 was significantly upregulated in patients and mice with DCM. In vivo experiments showed that targeted inhibition of cardiac SOCS2 could improve mouse cardiac function and alleviate myocardial fibrosis. Further research demonstrated that SOCS2 promoted the transformation of myofibroblasts. Knockdown of SOCS2 reduced the nuclear localization of β-catenin, which inhibited the fibrogenic effect of Wnt/β-catenin pathway. In addition, bioinformatics analysis suggested that lymphoid enhancer binding factor 1 (LEF1) was significantly positively correlated with SOCS2. Finally, dual luciferase assays demonstrated that LEF1 could bind to the promoter region of SOCS2, thereby mediating its transcriptional activation.
SOCS2 could activate the Wnt/β-catenin by regulating the nuclear translocation of β-catenin, which induces the transcriptional activation of SOCS2. Overall, these results indicated a positive feedback activation phenomenon between SOCS2, β-catenin and LEF1 in DCM. These results suggested that inhibition of SOCS2 could effectively alleviate the progression of myocardial fibrosis and improve cardiac function.
心肌纤维化是扩张型心肌病（DCM）的重要病理特征。SOCS2 在不同器官纤维化中的作用存在争议。在此，我们研究了 SOCS2 在心肌纤维化中的功能和潜在机制。
生物信息学、免疫组织化学（IHC）、免疫荧光（IF）、蛋白质印迹（WB）、实时荧光定量 PCR（qPCR）、大鼠原代心肌成纤维细胞（rCFs）培养、阿霉素（DOX）诱导的小鼠扩张型心肌病（DCM）模型以及体内腺相关病毒（AAV）感染用于探索 SOCS2 在 DCM 中的作用。
生物信息学分析表明 SOCS2 与纤维化相关因子呈正相关。SOCS2 在 DCM 患者和小鼠中显著上调。体内实验表明，心脏 SOCS2 的靶向抑制可改善小鼠心功能并减轻心肌纤维化。进一步研究表明 SOCS2 促进了肌成纤维细胞的转化。SOCS2 的敲低减少了β-catenin 的核定位，从而抑制了 Wnt/β-catenin 通路的成纤维作用。此外，生物信息学分析表明淋巴增强结合因子 1（LEF1）与 SOCS2 呈显著正相关。最后，双荧光素酶报告基因实验表明 LEF1 可以结合 SOCS2 的启动子区域，从而介导其转录激活。
SOCS2 可以通过调节β-catenin 的核转位来激活 Wnt/β-catenin，从而诱导 SOCS2 的转录激活。总体而言，这些结果表明在 DCM 中 SOCS2、β-catenin 和 LEF1 之间存在正反馈激活现象。这些结果表明抑制 SOCS2 可有效减轻心肌纤维化的进展并改善心功能。
