title: Arsenic promotes angiogenesis in vitro via a heme oxygenase-1-dependent mechanism.
abstract: 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 muM) 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.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; Shanghai, 200031, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Meng
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Chang
authors.forename: Andrew
authors.initials: A
authors.lastname: Hitron
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Binghua
authors.initials: B
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000633:toxicity*; D001151:Arsenic / Q000633:toxicity*; D018053:Arsenites / Q000633:toxicity; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D018053:Arsenites; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C015001:arsenite; D001151:Arsenic