Lefty1 Ameliorates Post-infarction Fibrosis by Suppressing p-Smad2 and p-ERK1/2 Signaling Pathways.

Transforming growth factor-β1 signaling pathways are known to involve in the development of post-infarction fibrosis, a process characterized by the aberrant activation, proliferation, and differentiation of fibroblasts, as well as the unbalanced turnover of extracellular matrix proteins. Recent studies have shown that Lefty1, a novel member of TGF-β superfamily, acts as a brake on the TGF-β signaling pathway in non-cardiac tissues. However, its role in myocardial infarction (MI)-induced fibrosis and left ventricular remodeling has not been fully elucidated. Here, for the first time, we reported that Lefty1 alleviated post-MI fibroblast proliferation, differentiation, and secretion through suppressing p-Smad2 and p-ERK1/2 signaling pathways in vivo and in vitro. In MI mice or TGF-β1-treated neonatal rat cardiac fibroblasts (CFBs), the expression of Lefty1 was upregulated. Adenovirus-mediated overexpression of Lefty1 significantly attenuated TGF-β1-induced CFBs' proliferation, differentiation, and collagen production. Using the adeno-associated virus approach, we confirmed that Lefty1 attenuates MI-induced cardiac injury, as evidenced by the decreased infarct size and preserved cardiac function. These results highlight the importance of Lefty1 in the prevention of post-MI fibrosis and may help identify potential targets for therapeutic intervention of cardiac fibrosis. Graphical abstract.