Low dose cadmium upregulates the expression of von Willebrand factor in endothelial cells

• Published in: Toxicology letters 2018-06, Vol.290, p.46-54
• Main Authors: Wang, Xia, Dong, Fengyun, Wang, Fufang, Yan, Suhua, Chen, Xiaocui, Tozawa, Hideto, Ushijima, Toshiyuki, Kapron, Carolyn M., Wada, Youichiro, Liu, Ju
• Format: Article
• Language: English
• Subjects: Animals; Cadmium; Cadmium - toxicity; Cells, Cultured; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; ERG; GATA3 Transcription Factor - genetics; Humans; Male; Mice; NF-kappa B - physiology; Oncogene Proteins - genetics; Signal Transduction - drug effects; Transcription; Transcriptional Regulator ERG - genetics; Up-Regulation; Von willebrand factor; von Willebrand Factor - genetics
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2018.03.020

•Low dose cadmium (Cd) exposure induces von Willebrand factor (vWF) expression in mouse vasculature.•Low dose Cd induces vWF expression and secretion in endothelial cells in vitro.•NF-κB and GATA3 signaling is not induced by low dose Cd in endothelial cells.•Transcription factor ERG mediates Cd-induced upregulation of vWF in endothelial cells. Cadmium (Cd) is a persistent and widespread environmental pollutant of continuing worldwide concern. Previous studies have suggested that Cd exposure increases the risk of cardiovascular diseases, such as atherosclerosis and hypertension. However, the underlying mechanisms are poorly understood. In this study, we observed that low dose Cd treatment induced von Willebrand factor (vWF) expression in vascular endothelial cells in mouse lung and kidney tissues. In vitro analysis showed that 1 μM Cd specifically upregulated vWF mRNA and protein expression in human umbilical vein endothelial cells (HUVECs), indicating that Cd targets vascular endothelial cells even at relatively low concentrations. Further study demonstrated that nuclear factor kappa B (NF-κB) and GATA3, two established transcription regulators of the vWF gene, were not altered in the presence of Cd. However, ETS-related gene (ERG) was significantly induced by 1 μM Cd. When ERG was knocked down by siRNA, Cd induced upregulation of vWF was totally blocked. Chromatin immunoprecipitation (ChIP) assay showed that Cd increases the binding of ERG on the −56 ETS motif on the human vWF promoter. These results indicated that ERG mediated the increased expression of vWF by Cd. Since vWF is a key regulator for vascular homeostasis, our findings may provide a novel mechanism for understanding low dose Cd induced development of vascular diseases.