Cargando…
Bach1-induced suppression of angiogenesis is dependent on the BTB domain
The transcription factor Bach1 impairs angiogenesis after ischemic injury by suppressing Wnt/β-catenin signaling; however, the specific domains responsible for the anti-angiogenic effects of Bach1 remain unclear. This study determined the role of the BTB domain of Bach1 in ischemic angiogenesis. Bac...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948167/ https://www.ncbi.nlm.nih.gov/pubmed/31911270 http://dx.doi.org/10.1016/j.ebiom.2019.102617 |
_version_ | 1783485696340656128 |
---|---|
author | Jiang, Li Jia, Mengping Wei, Xiangxiang Guo, Jieyu Hao, Shengyu Mei, Aihong Zhi, Xiuling Wang, Xinhong Li, Qinhan Jin, Jiayu Zhang, Jianyi Li, Shanqun Meng, Dan |
author_facet | Jiang, Li Jia, Mengping Wei, Xiangxiang Guo, Jieyu Hao, Shengyu Mei, Aihong Zhi, Xiuling Wang, Xinhong Li, Qinhan Jin, Jiayu Zhang, Jianyi Li, Shanqun Meng, Dan |
author_sort | Jiang, Li |
collection | PubMed |
description | The transcription factor Bach1 impairs angiogenesis after ischemic injury by suppressing Wnt/β-catenin signaling; however, the specific domains responsible for the anti-angiogenic effects of Bach1 remain unclear. This study determined the role of the BTB domain of Bach1 in ischemic angiogenesis. Bach1 is highly expressed in circulating endothelial cells from acute myocardial infarction patients and is the early induction gene after ischemia. Mice were treated with adenoviruses coding for GFP (AdGFP), Bach1 (AdBach1), or a Bach1 mutant lacking the BTB domain (AdBach1-ΔBTB) after surgically induced hind-limb ischemia. Measures of blood-flow recovery, capillary density, and the expression of vascular endothelial growth factor (VEGF) and heme oxygenase-1 (HO-1) were significantly lower and ROS levels were higher in the AdBach1 group, but not in AdBach1-ΔBTB animals. Furthermore, transfection with AdBach1, but not AdBach1-ΔBTB, in human endothelial cells was associated with significant declines in 1) capillary density and hemoglobin content in the Matrigel-plug assay, 2) proliferation, migration, tube formation, and VEGF and HO-1 expression in endothelial cells. Bach1 binds directly with TCF4, and this interaction is mediated by residues 81–89 of the Bach1 BTB domain and the N-terminal domain of TCF4. Bach1, but not Bach1-ΔBTB, also co-precipitated with histone deacetylase 1 (HDAC1), while the full-length HDAC1 proteins, but not HDAC1 mutants lacking the protein-interaction domain, co-precipitated with Bach1. Collectively, these results demonstrate that the anti-angiogenic activity of Bach1 is crucially dependent on molecular interactions that are mediated by the protein's BTB domain, and this domain could be a drug target for angiogenic therapy. |
format | Online Article Text |
id | pubmed-6948167 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-69481672020-01-09 Bach1-induced suppression of angiogenesis is dependent on the BTB domain Jiang, Li Jia, Mengping Wei, Xiangxiang Guo, Jieyu Hao, Shengyu Mei, Aihong Zhi, Xiuling Wang, Xinhong Li, Qinhan Jin, Jiayu Zhang, Jianyi Li, Shanqun Meng, Dan EBioMedicine Research paper The transcription factor Bach1 impairs angiogenesis after ischemic injury by suppressing Wnt/β-catenin signaling; however, the specific domains responsible for the anti-angiogenic effects of Bach1 remain unclear. This study determined the role of the BTB domain of Bach1 in ischemic angiogenesis. Bach1 is highly expressed in circulating endothelial cells from acute myocardial infarction patients and is the early induction gene after ischemia. Mice were treated with adenoviruses coding for GFP (AdGFP), Bach1 (AdBach1), or a Bach1 mutant lacking the BTB domain (AdBach1-ΔBTB) after surgically induced hind-limb ischemia. Measures of blood-flow recovery, capillary density, and the expression of vascular endothelial growth factor (VEGF) and heme oxygenase-1 (HO-1) were significantly lower and ROS levels were higher in the AdBach1 group, but not in AdBach1-ΔBTB animals. Furthermore, transfection with AdBach1, but not AdBach1-ΔBTB, in human endothelial cells was associated with significant declines in 1) capillary density and hemoglobin content in the Matrigel-plug assay, 2) proliferation, migration, tube formation, and VEGF and HO-1 expression in endothelial cells. Bach1 binds directly with TCF4, and this interaction is mediated by residues 81–89 of the Bach1 BTB domain and the N-terminal domain of TCF4. Bach1, but not Bach1-ΔBTB, also co-precipitated with histone deacetylase 1 (HDAC1), while the full-length HDAC1 proteins, but not HDAC1 mutants lacking the protein-interaction domain, co-precipitated with Bach1. Collectively, these results demonstrate that the anti-angiogenic activity of Bach1 is crucially dependent on molecular interactions that are mediated by the protein's BTB domain, and this domain could be a drug target for angiogenic therapy. Elsevier 2020-01-03 /pmc/articles/PMC6948167/ /pubmed/31911270 http://dx.doi.org/10.1016/j.ebiom.2019.102617 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research paper Jiang, Li Jia, Mengping Wei, Xiangxiang Guo, Jieyu Hao, Shengyu Mei, Aihong Zhi, Xiuling Wang, Xinhong Li, Qinhan Jin, Jiayu Zhang, Jianyi Li, Shanqun Meng, Dan Bach1-induced suppression of angiogenesis is dependent on the BTB domain |
title | Bach1-induced suppression of angiogenesis is dependent on the BTB domain |
title_full | Bach1-induced suppression of angiogenesis is dependent on the BTB domain |
title_fullStr | Bach1-induced suppression of angiogenesis is dependent on the BTB domain |
title_full_unstemmed | Bach1-induced suppression of angiogenesis is dependent on the BTB domain |
title_short | Bach1-induced suppression of angiogenesis is dependent on the BTB domain |
title_sort | bach1-induced suppression of angiogenesis is dependent on the btb domain |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948167/ https://www.ncbi.nlm.nih.gov/pubmed/31911270 http://dx.doi.org/10.1016/j.ebiom.2019.102617 |
work_keys_str_mv | AT jiangli bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT jiamengping bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT weixiangxiang bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT guojieyu bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT haoshengyu bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT meiaihong bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT zhixiuling bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT wangxinhong bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT liqinhan bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT jinjiayu bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT zhangjianyi bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT lishanqun bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain AT mengdan bach1inducedsuppressionofangiogenesisisdependentonthebtbdomain |