Bach1-induced suppression of angiogenesis is dependent on the BTB domain
Bach1-induced suppression of angiogenesis is dependent on the BTB domain
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Bach1 诱导的血管生成抑制依赖于 BTB 结构域
DOI：
10.1016/j.ebiom.2019.102617
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发表时间：
2020-01-01
期刊：
影响因子：
11.1
通讯作者：
Meng, Dan
中科院分区：
文献类型：
--
作者：
Jiang, Li;Jia, Mengping;Meng, Dan
转录因子Bach1通过抑制Wnt/ β -连环蛋白信号通路影响缺血性损伤后血管生成；然而，Bach1抗血管生成作用的具体结构域尚不清楚。本研究确定了Bach1的BTB结构域在缺血性血管生成中的作用。Bach1在急性心肌梗死患者的循环内皮细胞中高表达，是缺血后的早期诱导基因。用编码GFP （AdGFP）、Bach1 （AdBach1）或缺乏BTB结构域的Bach1突变体（AdBach1- delta BTB）的腺病毒治疗手术诱导的小鼠后肢缺血。AdBach1组的血流量恢复、毛细血管密度、血管内皮生长因子（VEGF）和血红素氧合酶-1 （HO-1）的表达显著降低，ROS水平显著升高，但AdBach1- delta BTB动物无此现象。此外，在人内皮细胞中转染AdBach1，而不是AdBach1- delta BTB，与1)毛细血管密度和血红蛋白含量显著下降相关，在基质堵塞试验中，2)内皮细胞的增殖、迁移、管形成以及VEGF和HO-1表达显著下降。Bachl直接与TCF4结合，这种相互作用是由Bachl BTB结构域和TCF4 n端结构域的残基81-89介导的。Bachl，而不是Bach1-Delta BTB，也与组蛋白去乙酰化酶1 （HDAC1）共沉淀，而全长HDAC1蛋白，而不是缺乏蛋白质相互作用结构域的HDAC1突变体，与Bachl共沉淀。总的来说，这些结果表明Bachl的抗血管生成活性主要依赖于由该蛋白的BTB结构域介导的分子相互作用，该结构域可能是血管生成治疗的药物靶点。(C) 2019作者。Elsevier B.V.出版
The transcription factor Bach1 impairs angiogenesis after ischemic injury by suppressing Wnt/beta-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-Delta BTB) 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-Delta BTB animals. Furthermore, transfection with AdBach1, but not AdBach1-Delta BTB, 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. Bachl binds directly with TCF4, and this interaction is mediated by residues 81-89 of the Bachl BTB domain and the N-terminal domain of TCF4. Bachl, but not Bach1-Delta BTB, 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 Bachl. Collectively, these results demonstrate that the anti-angiogenic activity of Bachl 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. (C) 2019 The Author(s). Published by Elsevier B.V.