Arsenic promotes angiogenesis in vitro via a heme oxygenase-1-dependent mechanism
Arsenic promotes angiogenesis in vitro via a heme oxygenase-1-dependent mechanism
复制标题
砷通过血红素加氧酶 1 依赖性机制促进体外血管生成
DOI：
10.1016/j.taap.2010.01.004
复制
发表时间：
2010-05-01
影响因子：
3.8
通讯作者：
Shi, Xianglin
中科院分区：
文献类型：
--
作者：
Meng, Dan;Wang, Xin;Shi, Xianglin
血管生成和血管重塑是环境砷暴露引起的许多疾病（包括肿瘤和心血管疾病）发病机制的基础。砷（AsIII）已被证明在体内刺激血管生成和血管重塑。然而，砷诱导血管生成的确切分子机制尚不清楚。本研究探讨血红素氧合酶-1（HO-1）在亚砷酸钠介导的血管生成中的作用。采用Transwell法、三维Matrigel法、RT-PCR法、ELISA法和免疫印迹法检测细胞迁移、血管形成、mRNA和蛋白表达。染色质免疫沉淀法和荧光素酶法检测DNA与蛋白质的结合及HO-1的转录活性。在这里，我们报告说，低浓度的亚砷酸盐（0.1-1 μ M）刺激细胞迁移和血管形成在人微血管内皮细胞（HMVEC）。亚砷酸钠诱导HO-1 mRNA和蛋白表达。敲低HO-1表达可降低亚砷酸盐诱导的VEGF表达、细胞迁移和管形成。我们发现，亚砷酸盐促进解离Bach 1（转录抑制因子）从HO-1增强子和增加Nrf 2结合这些元素。定点突变实验表明，Bach 1半胱氨酸残基557和574是诱导HO-1基因响应亚砷酸盐的关键。这些发现表明HO-1在亚砷酸盐介导的体外血管生成中的作用。(C)2010年爱思唯尔公司All rights reserved.
Angiogenesis and vessel remodeling are fundamental to the pathogenesis of a number of diseases caused by environmental arsenic exposure, including tumorigenesis and cardiovascular diseases. Arsenic (AsIII) has been shown to stimulate angiogenesis and vascular remodeling in vivo. However, the exact molecular mechanisms accounting for arsenic-induced angiogenesis are not clear. The present study investigates the role of heme oxygenase-1 (HO-1) in sodium arsenite-mediated angiogenesis in vitro. Transwell assay, three-dimensional Matrigel assay, RT-PCR, ELISA and immunoblotting were used to determine cell migration, vascular tube formation, mRNA and protein expression. Chromatin immunoprecipitation and luciferase assay were applied to examine the DNA binding with protein and HO-1 transcriptional activity. Here, we report that low concentrations of arsenite (0.1-1 mu M) stimulated cell migration and vascular tube formation in human microvascular endothelial cells (HMVEC). Arsenite induced HO-1 mRNA and protein expression. Knock down of HO-1 expression decreased arsenite-induced VEGF expression, cell migration, and tube formation. We showed that arsenite promoted dissociation of Bach1 (a transcriptional repressor) from the HO-1 enhancers and increased Nrf2 binding to these elements. Site directed mutagenesis assay identified that Bach1 cysteine residues 557 and 574 were essential for the induction of HO-1 gene in response to arsenite. These findings demonstrate a role for HO-1 in arsenite-mediated angiogenesis in vitro. (C) 2010 Elsevier Inc. All rights reserved.