Related Experiment Video
Updated: Feb 28, 2026
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Serpine1 Regulates the Enhanced Inhibitory Effect of CHIR99021 Combined with Fibroblast Growth Factor 2 on Myocardial
Yangyang Jia1, Xiangqin Tian1, Mengyu Wei1
1Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang 453003, China.
Abstract:
Cardiac fibrosis is a pathological phenomenon caused by tissue remodeling and excessive matrix proliferation under stress conditions. CHIR99021 is a selective glycogen synthase kinase-3 inhibitor that has shown potential in cardiovascular regeneration therapy. Fibroblast growth factor 2 (FGF2) has a protective effect on ischemic myocardium. However, the effect and underlying mechanism of the combined use of CHIR99021 and FGF2 on myocardial fibrosis remains unclear. In this study, we found that the combination of CHIR99021 and FGF2 could significantly inhibit the activation of cardiac fibroblasts (CFs) and alleviate the formation of collagen scars in mouse myocardium. By analyzing the expression levels of fibrotic proteins, such as ColI, ColIII and alpha smooth muscle actin (α-SMA) in fibroblasts in vitro and in vivo, we confirmed the inhibitory effect of CHIR99021 combined with FGF2 on the activation of fibroblasts. Transcriptome sequencing showed that CHIR99021 and FGF2 inhibited the expression level of Serpine1 through the transforming growth factor-β (TGF-β) and Focal Adhesion Kinase (FAK) signaling pathways. By analyzing the regulatory effect of overexpressed and knocked-down Serpine1 on fibrotic pathway-related proteins in CFs, we verified that Serpine1 is a key target for inhibiting fibrosis. In conclusion, this study provides evidence that Serpine1 may be a potential mechanism that enables CHIR99021 combined with FGF2 to improve myocardial fibrosis.
Insights
Combining CHIR99021 and Fibroblast Growth Factor 2 (FGF2) inhibits cardiac fibroblast activation and collagen scar formation. This combination therapy targets Serpine1, offering a potential mechanism to treat myocardial fibrosis.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Fibrosis Research
Background:
- Cardiac fibrosis, characterized by excessive matrix deposition, contributes to heart dysfunction.
- CHIR99021 (glycogen synthase kinase-3 inhibitor) and FGF2 show promise in cardiovascular regeneration.
- The combined effects and mechanisms of CHIR99021 and FGF2 on myocardial fibrosis are not well understood.
Purpose of the Study:
- To investigate the combined effect of CHIR99021 and FGF2 on myocardial fibrosis.
- To elucidate the underlying molecular mechanisms, focusing on fibroblast activation and matrix production.
Main Methods:
- In vitro and in vivo studies using cardiac fibroblasts (CFs) and mouse myocardium.
- Analysis of fibrotic protein expression (ColI, ColIII, α-SMA).
- Transcriptome sequencing and pathway analysis (TGF-β, FAK).
- Functional studies involving Serpine1 overexpression and knockdown.
Main Results:
- CHIR99021 and FGF2 significantly inhibited CF activation and collagen scar formation.
- The combination therapy reduced expression of fibrotic markers ColI, ColIII, and α-SMA.
- Transcriptome analysis revealed inhibition of Serpine1 via TGF-β and FAK pathways.
- Serpine1 was identified as a key target in mitigating fibrosis.
Conclusions:
- Combined CHIR99021 and FGF2 effectively inhibit cardiac fibroblast activation and myocardial fibrosis.
- Serpine1 acts as a crucial mediator in the antifibrotic effects of this combination therapy.
- This study identifies Serpine1 as a potential therapeutic target for improving myocardial fibrosis.
