Li Jiang1, Meng Yin1, Xiangxiang Wei1, Junxu Liu1, Xinhong Wang1, Cong Niu1, Xueling Kang1, Jie Xu1, Zhongwei Zhou1, Shaoyang Sun1, Xu Wang1, Xiaojun Zheng1, Shengzhong Duan1, Kang Yao1, Ruizhe Qian1, Ning Sun1, Alex Chen1, Rui Wang1, Jianyi Zhang1, Sifeng Chen1, Dan Meng1. 1. Department of Physiology and Pathophysiology (L.J., Xiangxiang Wei, J.L., Xinhong Wang, C.N., X.K., J.X., Z.Z., R.Q., N.S., A.C., R.W., S.C., D.M.) and Department of Biochemistry and Molecular Biology (S.S., Xu Wang), School of Basic Medical Sciences, Fudan University, Shanghai, China; Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China (M.Y.); Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (X.Z., S.D.); Department of Cardiology, Shanghai Institute of Cardiovascular Disease, ZhongShan Hospital, Fudan University, Shanghai, China (K.Y.); Center for Vascular Disease and Translational Medicine, Xiangya Third Hospital, Central South University, Changsha, China (A.C.); Department of Biology, Laurentian University, Sudbury, Ontario, Canada (R.W.); and Division of Cardiology, Department of Medicine, Stem Cell Institute, University of Minnesota Medical School, Minneapolis (J.Z.).
Abstract
RATIONALE: 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. OBJECTIVE: This study evaluated the role of Bach1 in angiogenesis and Wnt/β-catenin signaling. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
RATIONALE: 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. OBJECTIVE: This study evaluated the role of Bach1 in angiogenesis and Wnt/β-catenin signaling. METHODS AND RESULTS: 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. CONCLUSIONS: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.
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