The metastasis-associated protein MTA3 promotes cardiac repair by inhibiting the fibroblast to myofibroblast transition during fibrosis.

Cardiac fibrosis is a pathological hallmark of various cardiovascular disorders. Accumulating evidence has demonstrated that fibroblasts transform into myofibroblasts during the occurrence of cardiac fibrosis, but the mechanism remains incompletely understood. This study aims to investigate the relevance of MTA3 as a potential therapeutic target for cardiac fibrosis. The myocardial infarction model was established by ligating the left coronary artery of C57BL6 mice, and myocardial fibrosis was measured by cardiac ultrasound and Sirius red staining of myocardium. MTA3 overexpression plasmid was constructed and transfected into primary fibroblasts, immunofluorescence, Western blot and qRT-PCR were used to detect the expression of MTA3, α-SMA, and Collagen I. RNAi was used to interfere with the downstream potential target gene E2F1. SB203580, a specific inhibitor of p38 MAPK, reduced the levels of phosphorylated p38 MAPK (p-p38) by inhibiting p38 MAPK activity, and allowed assessment of MTA3-induced fibroblast to myofibroblast transformation. The expression of MTA3 was reduced in fibrotic myocardium. Overexpression of MTA3 could restore cardiac function. During the transformation process of cardiac fibroblasts into myofibroblasts, the expression of MTA3 was downregulated. After overexpression of MTA3, the mRNA and protein levels of α-SMA and Collagen I were significantly reduced. When E2F1 was disrupted, the mRNA and protein levels of α-SMA and Collagen I were downregulated. Inhibition of p-p38 MAPK expression by SB203580 ameliorated myocardial fibrosis. MTA3 regulates the transformation of fibroblast into myofibroblast by p38 MAPK-E2F1 signaling pathway, and MTA3 may become a potential target for treating cardiac fibrosis.