Bach1 Represses Wnt/β-Catenin Signaling and Angiogenesis.
Wnt/β-catenin signaling has an important role in the angiogenic activity of endothelial cells (ECs). Bach1 is a transcription factor and is expressed in ECs, but whether Bach1 regulates angiogenesis is unknown.This study evaluated the role of Bach1 in angiogenesis and Wnt/β-catenin signaling.Hind-limb ischemia was surgically induced in Bach1(-/-) mice and ... their wild-type littermates and in C57BL/6J mice treated with adenoviruses coding for Bach1 or GFP. Lack of Bach1 expression was associated with significant increases in perfusion and vascular density and in the expression of proangiogenic cytokines in the ischemic hindlimb of mice, with enhancement of the angiogenic activity of ECs (eg, tube formation, migration, and proliferation). Bach1 overexpression impaired angiogenesis in mice with hind-limb ischemia and inhibited Wnt3a-stimulated angiogenic response and the expression of Wnt/β-catenin target genes, such as interleukin-8 and vascular endothelial growth factor, in human umbilical vein ECs. Interleukin-8 and vascular endothelial growth factor were responsible for the antiangiogenic response of Bach1. Immunoprecipitation and GST pull-down assessments indicated that Bach1 binds directly to TCF4 and reduces the interaction of β-catenin with TCF4. Bach1 overexpression reduces the interaction between p300/CBP and β-catenin, as well as β-catenin acetylation, and chromatin immunoprecipitation experiments confirmed that Bach1 occupies the TCF4-binding site of the interleukin-8 promoter and recruits histone deacetylase 1 to the interleukin-8 promoter in human umbilical vein ECs.Bach1 suppresses angiogenesis after ischemic injury and impairs Wnt/β-catenin signaling by disrupting the interaction between β-catenin and TCF4 and by recruiting histone deacetylase 1 to the promoter of TCF4-targeted genes.
Mesh Terms:
Acetylation, Animals, Apoptosis, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Basic-Leucine Zipper Transcription Factors, Binding Sites, Cell Movement, Cell Proliferation, Disease Models, Animal, Down-Regulation, Endothelial Cells, Fanconi Anemia Complementation Group Proteins, Female, HEK293 Cells, Hindlimb, Histone Deacetylase 1, Human Umbilical Vein Endothelial Cells, Humans, Interleukin-8, Ischemia, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Muscle, Skeletal, Neovascularization, Physiologic, Promoter Regions, Genetic, Protein Binding, RNA Interference, Transcription Factors, Transfection, Vascular Endothelial Growth Factor A, Wnt Signaling Pathway, Wnt3A Protein, beta Catenin, p300-CBP Transcription Factors
Acetylation, Animals, Apoptosis, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Basic-Leucine Zipper Transcription Factors, Binding Sites, Cell Movement, Cell Proliferation, Disease Models, Animal, Down-Regulation, Endothelial Cells, Fanconi Anemia Complementation Group Proteins, Female, HEK293 Cells, Hindlimb, Histone Deacetylase 1, Human Umbilical Vein Endothelial Cells, Humans, Interleukin-8, Ischemia, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Muscle, Skeletal, Neovascularization, Physiologic, Promoter Regions, Genetic, Protein Binding, RNA Interference, Transcription Factors, Transfection, Vascular Endothelial Growth Factor A, Wnt Signaling Pathway, Wnt3A Protein, beta Catenin, p300-CBP Transcription Factors
Circ. Res.
Date: Jul. 31, 2015
PubMed ID: 26123998
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