TGF-β1-induced SMAD2/3/4 activation promotes RELM-β transcription to modulate the endothelium-mesenchymal transition in human endothelial cells

Endothelial-to-mesenchymal transition (EndMT), which is characterized by increased proliferation, migration and invasion of endothelial cells, increased expression of mesenchymal markers and reduced expression of endothelial markers, has been reported to be closely related to the pathogenesis of several diseases, including pulmonary fibrosis. Resistin-like molecule-beta (RELM-beta), also known as found in inflammatory zone 2 '' (FIIZ2), plays an essential role in airway remodeling and pulmonary fibrosis; however, its role and mechanism in EndMT remain unclear. Herein, we used TGF-beta 1-induced EndMT cell model in human umbilical vein endothelial cells (HUVECs) and human primary pulmonary artery endothelial cells (HPAECs) to investigate the function and mechanism of RELM-D in TGF-beta 1-induced EndMT in endothelial cell lines. We found that TGF-beta 1 stimulation significantly upregulated RELM-beta expression; RELM-beta knockdown could attenuate TGF-beta 1-induced cell proliferation and migration of endothelial cell lines and changes in protein levels of EndMT markers. SB432542, an inhibitor of SMADs, could partially reverse TGF-beta 1-induced RELM-beta-expression, endothelial cell migration and changes in EndMT marker protein levels. SMADs complex exerted its effects through SMAD2/3/4 complex mediating RELM-beta transcription. In conclusion, TGF-beta 1 induces RELM-beta transcription to promote EndMT in HUVECs and HPAECs through activation of SMAD2/3/4; blocking SMADs-mediated REIM-beta transcription might ameliorate TGE-beta 1-induced EndMT in endothelial cells.