Bach1 Represses Wnt/β-Catenin Signaling and Angiogenesis.
Bach1 Represses Wnt/β-Catenin Signaling and Angiogenesis.
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DOI：
10.1161/circresaha.115.306829
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发表时间：
2015-07-31
影响因子：
20.1
通讯作者：
Meng D
中科院分区：
文献类型：
--
作者：
Jiang L;Yin M;Wei X;Liu J;Wang X;Niu C;Kang X;Xu J;Zhou Z;Sun S;Wang X;Zheng X;Duan S;Yao K;Qian R;Sun N;Chen A;Wang R;Zhang J;Chen S;Meng D
Wnt/β-catenin信号通路在内皮细胞的血管生成活性中起重要作用。Bach 1是一种转录因子，在内皮细胞中表达，但Bach 1是否调节血管生成尚不清楚。本研究评价了Bach 1在血管生成和Wnt/β-catenin信号传导中的作用。在Bach 1 −/−小鼠及其野生型同窝出生的小鼠中，以及用编码Bach 1或GFP的腺病毒处理的C57 BL/6 J小鼠中，通过手术诱导后肢缺血。Bach 1表达的缺乏与灌注和血管密度的显著增加以及小鼠缺血后肢中促血管生成细胞因子的表达相关，并增强了EC的血管生成活性（例如，管形成、迁移和增殖）。Bach 1过表达可损害后肢缺血小鼠的血管生成，并抑制Wnt 3a刺激的血管生成反应和人脐静脉EC中Wnt/β-catenin靶基因（如白细胞介素-8和血管内皮生长因子）的表达。白细胞介素-8和血管内皮生长因子负责Bach 1的抗血管生成反应。免疫沉淀和GST pull-down评估表明Bach 1直接与TCF 4结合，并减少β-catenin与TCF 4的相互作用。Bach 1过表达降低了p300/CBP和β-catenin之间的相互作用，以及β-catenin乙酰化，染色质免疫沉淀实验证实，Bach 1占据了白细胞介素-8启动子的TCF 4结合位点，并在人脐静脉EC中将组蛋白脱乙酰酶1募集到白细胞介素-8启动子。Bach 1通过破坏β-catenin和TCF 4之间的相互作用以及通过将组蛋白去乙酰化酶1募集到TCF 4靶向基因的启动子来抑制缺血性损伤后的血管生成并损害Wnt/β-catenin信号传导。
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.