Arsenic promotes angiogenesis in vitro via a heme oxygenase-1-dependent mechanism

• Published in: Toxicology and applied pharmacology Vol. 244; no. 3; pp. 291 - 299
• Main Authors: Meng, Dan, Wang, Xin, Chang, Qingshan, Hitron, Andrew, Zhang, Zhuo, Xu, Mei, Chen, Gang, Luo, Jia, Jiang, Binghua, Fang, Jing, Shi, Xianglin
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.05.2010; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ALKALI METALS; AMINO ACIDS; ANGIOGENESIS; Angiogenesis Inducing Agents - toxicity; ANIMALS; ARSENIC; Arsenic - toxicity; Arsenites - toxicity; Bach1; Basic-Leucine Zipper Transcription Factors - metabolism; BIOASSAY; Biological and medical sciences; CARBOXYLIC ACIDS; Carcinogenesis, carcinogens and anticarcinogens; CARDIOVASCULAR DISEASES; Cell Movement - drug effects; Cells, Cultured; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; CHROMATIN; CYSTEINE; DISEASES; DNA; ELEMENTS; Endothelial; Endothelial Cells - drug effects; Endothelial Cells - metabolism; ENZYME IMMUNOASSAY; ENZYMES; Fanconi Anemia Complementation Group Proteins - metabolism; Gene Expression Regulation - drug effects; GENES; GROWTH FACTORS; HEME; Heme oxygenase 1; Heme Oxygenase-1 - metabolism; HETEROCYCLIC ACIDS; HETEROCYCLIC COMPOUNDS; Humans; IMMUNOASSAY; IN VITRO; LUCIFERASE; MALES; MAMMALS; MAN; MAP Kinase Kinase 4 - metabolism; Medical sciences; MEN; MESSENGER-RNA; METALS; Metals and various inorganic compounds; Microvessels - drug effects; Microvessels - metabolism; MITOGENS; MUTAGENESIS; Neovascularization, Physiologic - drug effects; NF-E2-Related Factor 2 - metabolism; Nrf2; NUCLEIC ACIDS; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANIC SULFUR COMPOUNDS; OXIDASES; OXIDOREDUCTASES; OXYGENASES; p38 Mitogen-Activated Protein Kinases - metabolism; PATHOGENESIS; Phosphatidylinositol 3-Kinases - metabolism; PIGMENTS; PORPHYRINS; PRIMATES; Protein Kinase C - metabolism; PROTEINS; Reactive Oxygen Species - metabolism; RNA; RNA, Messenger - metabolism; SEMIMETALS; SODIUM; THIOLS; Toxicology; Tumors; Vascular Endothelial Growth Factor A - metabolism; VERTEBRATES; Angiogenesis; Bach1; Heme oxygenase 1; Maf; MARE; Arsenic; Nrf2; HMVECs; VEGF; Endothelial; HO-1; ChIP; Endothelial cell; Enzyme; Heme oxygenase (decyclizing); In vitro; Endothelium; Carcinogen; Heat shock protein; Oxidoreductases; Neovascularization; Mechanism of action
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2010.01.004

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 μM) 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.