MFGE8 is down-regulated in cardiac fibrosis and attenuates endothelial-mesenchymal transition through Smad2/3-Snail signalling pathway.

Abstract

Endothelial‐mesenchymal transition (EndMT) is a major source of transformed cardiac fibroblasts, which is reported to play a key role in cardiac fibrosis (CF), a pathogenesis of cardiovascular diseases such as heart failure, myocardial infarction and atrial fibrillation. Nonetheless, the specific mechanism underlying the progression of EndMT to CF is still largely unknown. In this study, we aimed to investigate the role of milk fat globule‐EGF factor 8 (MFGE8), a kind of soluble glycoprotein, in TGF‐β1‐induced EndMT. In animal experiments, the expression of MFGE8 was found down‐regulated in the left ventricle and aorta of rats after transverse aortic constriction (TAC) compared with the sham group, especially in endothelial cells (ECs). In in vitro cultured ECs, silencing MFGE8 with small interfering RNA (siRNA) was found to promote the process of TGF‐β1‐induced EndMT, whereas administration of recombinant human MFGE8 (rh‐MFGE8) attenuated the process. Moreover, activated Smad2/3 signalling pathway after TGF‐β1 treatment and EndMT‐related transcription factors, such as Snail, Twist and Slug, was potentiated by MFGE8 knock‐down but inhibited by rh‐MFGE8. In conclusion, our experiments indicate that MFGE8 might play a protective role in TGF‐β1‐induced EndMT and might be a potential therapeutic target for cardiac fibrosis.