Tumor necrosis factor‐α stimulation endothelial‐to‐mesenchymal transition during cardiac fibrosis via endothelin‐1 signaling

Abstract

AbstractCardiac fibrosis is an important pathological change after myocardial infarction (MI). High concentration of tumor necrosis factor‐α (TNF‐α) contributes to cardiac fibrosis, and TNF‐α has been demonstrated to be involved in transforming growth factor‐β1‐induced endothelial‐to‐mesenchymal transition (EndMT). However, the role and molecular mechanisms of TNF‐α during cardiac fibrosis remain largely unexplored. In this study, we demonstrated that TNF‐α and endothelin‐1 (ET‐1) were upregulated in cardiac fibrosis after MI, and genes associated with EndMT were also upregulated. An in vitro model of EndMT demonstrated that TNF‐α promoted EndMT by upregulation of vimentin and α‐smooth muscle actin, and which strongly increased ET‐1 expression. ET‐1 promoted TNF‐α‐induced expression of gene program through phosphorylation levels of SMAD family member 2, while subsequent inhibition of ET‐1 almost abolished the effect of TNF‐α during the process of EndMT. In summary, these findings demonstrated that ET‐1 is involved in the EndMT induced by TNF‐α during cardiac fibrosis.