Foxm1 is a critical driver of TGF-?-induced EndMT in endothelial cells through Smad2/3 and binds to the Snail promoter.

ABSTRACT: Endothelial-to-mesenchymal transition (EndMT) was first reported in heart development. Recent studies have shown that EndMT also occurs in the progression of cardiac fibrosis. Herein, we demonstrated a critical role of the Forkhead Box M1 (Foxm1) transcription factor in transforming growth factor beta (TGF-?)-induced EndMT in endothelial cells (ECs) and a possible underlying molecular mechanism. Foxm1 was induced in ECs following TGF-? stimulation. Using both pharmacological and molecular approaches to inhibit Foxm1 function can attenuate the TGF-?-induced EndMT and cell migration. In contrast, lentivirus-mediated overexpression of Foxm1 allowed EndMT to proceed despite the absence of TGF-? in ECs. Moreover, we found that the activation of the Smad2/3 signaling pathway and EndMT-related transcription factors played important roles in the pathogenesis of Foxm1-mediated EndMT. Further analysis revealed that Foxm1 bound to and increased the promoter activity of the Snail gene encoding a critical transcriptional regulator of EndMT. In conclusion, our results identify FOXM1 as a driver of TGF-?-induced EndMT and underscore the therapeutic potential of targeting FOXM1 for cardiac fibrosis.

SUBMITTER: Song S 

PROVIDER: S-EPMC6686160 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature