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Updated: Jun 18, 2025
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Targeting SOCS2 alleviates myocardial fibrosis by reducing nuclear translocation of β-catenin
Ming Yuan1, Hongjie Shi1, Bin Wang2
1Department 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.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Suppressing SOCS2 alleviates myocardial fibrosis in dilated cardiomyopathy. This study reveals SOCS2 activates the Wnt/β-catenin pathway, promoting fibrosis through a positive feedback loop with LEF1.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Fibrosis Research
Background:
- Myocardial fibrosis is a key feature of dilated cardiomyopathy (DCM).
- The role of Suppressor of Cytokine Signaling 2 (SOCS2) in organ fibrosis is debated.
- This study investigates SOCS2's function and mechanism in myocardial fibrosis.
Purpose of the Study:
- To elucidate the role of SOCS2 in the pathogenesis of dilated cardiomyopathy (DCM).
- To explore the underlying molecular mechanisms by which SOCS2 influences myocardial fibrosis.
- To assess the therapeutic potential of targeting SOCS2 in DCM.
Main Methods:
- Bioinformatic analysis, immunohistochemistry, immunofluorescence, and Western blotting were employed.
- Primary rat cardiac fibroblasts and a doxorubicin-induced mouse model of DCM were utilized.
- In vivo gene manipulation using adeno-associated virus (AAV) vectors was performed.
Main Results:
- SOCS2 expression positively correlated with fibrosis markers and was upregulated in DCM.
- Inhibition of cardiac SOCS2 improved cardiac function and reduced myocardial fibrosis in mice.
- SOCS2 promotes myofibroblast differentiation and activates the Wnt/β-catenin pathway by regulating β-catenin nuclear translocation.
- LEF1 was identified as a transcriptional activator of SOCS2, forming a positive feedback loop.
Conclusions:
- SOCS2 plays a critical role in promoting myocardial fibrosis in DCM.
- A positive feedback loop involving SOCS2, β-catenin, and LEF1 drives DCM progression.
- Targeting SOCS2 represents a potential therapeutic strategy to alleviate myocardial fibrosis and improve cardiac function in DCM.
