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논문분류	춘계학술대회 초록집
제목	High-Mobility Group Box Protein 1 (HMGB1) Induces Endothelial-to-Mesenchymal Transition (EndMT) in Human Umbilical Vein Endothelial Cells (HUVEC)
저자	Jeong-Sun Han* 1, Yong-Soo Kim1
출판정보	2016; 2016(1):
키워드	Endothelial-to-Mesenchymal Transition (EndMT), HMGB1, Human Umbilical Vein Endothelial Cells (HUVEC)
초록	Background: Myofibroblasts are the major cells within the venous neointima in stenosed hemodialysis vascular access. In our previous study, oxidative stress stimulated HMGB1 expression in HUVEC. In this study, we investigated whether HMGB1 induced EndMT in HUVEC. Methods: After stimulating the HUVEC with HMGB1, the key biomarkers for endothelial and mesenchymal cells were evaluated by fluorescent immunocytochemistry and western blot. Role of HMGB1 receptors (TLR4 and RAGE), EndMT transcription factors (snail1, snail2, and twist1), and TGF-ß1 in the mechanism of HMGB1-induced EndMT was studied by western blot. Results: In the immunocytochemistry experiments, HUVEC in the absence of HMGB1 showed strong labeling of CD31, VE-cadherin, and von Willebrand factor predominantly to the cell membrane. α-SMA was not expressed and cells were normal round shape with cobble stone appearance. HUVEC exposed to HMGB1 showed a decrease in the endothelial proteins CD31, VE-cadherin, and von Willebrand factor. Furthermore, mesenchymal marker, α-SMA was significantly expressed and cells were spindle-shaped. These changes in biomarkers before and after HMGB1 treatment were reexamined by western blot, which gave same results. When the cells were pre-incubated with antibodies to HMGB1 receptors, TLR4 or RAGE, the changes in the HMGB1-induced endothelial and mesenchymal biomarkers were reversed in a dose dependent manner. HMGB1 stimulated the expression of EndMT transcription factors snail1, snail2, and twist1 in a time dependent manner up to 48 hours. In addition, HMGB1 stimulated the expression of TGF-ß1, and the phosphorylation of smad2/smad3 and NF-κB p65, which were peak at 24 hours. When the cells were pre-incubated with TGF-ß1 antibody, SB431542, the changes in the HMGB1-induced endothelial and mesenchymal biomarkers were reversed in a dose dependent manner. Conclusion: To our knowledge, this is the first report showing that HMGB1 induces EndMT via TGF-β1 secretion in the venous endothelial cells. These data will be useful to determine the mechanism of myofibroblasts accumulation within the venous neointima in stenosed hemodialysis vascular access.
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