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-β (RELM-β), 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-β1-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-β in TGF-β1-induced EndMT in endothelial cell lines. We found that TGF-β1 stimulation significantly upregulated RELM-β expression; RELM-β knockdown could attenuate TGF-β1-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-β1-induced RELM-β expression, endothelial cell migration and changes in EndMT marker protein levels. SMADs complex exerted its effects through SMAD2/3/4 complex mediating RELM-β transcription. In conclusion, TGF-β1 induces RELM-β transcription to promote EndMT in HUVECs and HPAECs through activation of SMAD2/3/4; blocking SMADs-mediated RELM-β transcription might ameliorate TGF-β1-induced EndMT in endothelial cells.

Jiang Y ，Zhou X ，Hu R ，Dai A ... -  《-》

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

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-β)-induced EndMT in endothelial cells (ECs) and a possible underlying molecular mechanism. Foxm1 was induced in ECs following TGF-β stimulation. Using both pharmacological and molecular approaches to inhibit Foxm1 function can attenuate the TGF-β-induced EndMT and cell migration. In contrast, lentivirus-mediated overexpression of Foxm1 allowed EndMT to proceed despite the absence of TGF-β 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-β-induced EndMT and underscore the therapeutic potential of targeting FOXM1 for cardiac fibrosis.

Song S ，Zhang R ，Cao W ，Fang G ，Yu Y ，Wan Y ，Wang C ，Li Y ，Wang Q ... -  《-》

Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling.

Hong L ，Li F ，Tang C ，Li L ，Sun L ，Li X ，Zhu L ... -  《-》

Apolipoprotein A1 Inhibits the TGF-β1-Induced Endothelial-to-Mesenchymal Transition of Human Coronary Artery Endothelial Cells.

Transforming growth factor β1 (TGF-β1) is the major cytokine for stimulating endothelial cells (ECs) to transdifferentiate to mesenchymal cells (MCs) in the process known as endothelial-to-mesenchymal transition (EndMT). Recently, TGF-β1-induced EndMT has been implicated in the pathogenesis of atherosclerosis (AS). It has been identified that apolipoprotein A1 (ApoA-I) obstructs TGF-β1-induced endothelial dysfunction, providing a protective effect for ECs and also anti-AS activity. However, the exact role of ApoA-I in TGF-β1-induced EndMT is not clear. In this study, we aimed to investigate whether ApoA-I can modulate TGF-β1-induced EndMT in human coronary artery ECs (HCAECs). The HCAECs were treated with TGF-β1 with or without ApoA-I. Morphological changes in HCAECs and the expression of EndMT-related markers were evaluated. HCAECs treated with TGF-β1 were found to transform to MC morphology, with inconspicuous expression of EC markers such as vascular endothelial cadherin and CD31, and conspicuous expression of fibroblast-specific protein 1 (FSP-1) and α-smooth muscle actin. The treatment of HCAECs with ApoA-I inhibited the TGF-β1-induced EndMT, and elevated expression of EC markers was observed but reduced expression of MC markers. Moreover, ApoA-I impeded the expression level of Slug and Snail, crucial transcriptional factors of EndMT, and it inhibited the TGF-β1-induced phosphorylation of Smad2 and Smad3 which affected the EC morphology. In addition, the knockdown of ABCA1 by RNA interference eliminated the inhibition effect of ApoA-I on TGF-β1-induced EndMT. Our findings revealed a novel mechanism for the ApoA-I protective effect on endothelium function via the inhibition of TGF-β1-induced EndMT. This might provide new insights for developing strategies for modulating AS and vascular remodeling.

Feng J ，Zhang J ，Jackson AO ，Zhu X ，Chen H ，Chen W ，Gui Q ，Yin K ... -  《-》

CXCR7 attenuates the TGF-β-induced endothelial-to-mesenchymal transition and pulmonary fibrosis.

Guan S ，Zhou J 《-》