Serpine1 Regulates the Enhanced Inhibitory Effect of CHIR99021 Combined with Fibroblast Growth Factor 2 on Myocardial Fibrosis After Myocardial Infarction in Mice.

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.