title: Disruption of canonical TGFβ-signaling in murine coronary progenitor cells by low level arsenic.
abstract: Exposure to arsenic results in several types of cancers as well as heart disease. A major contributor to ischemic heart pathologies is coronary artery disease, however the influences by environmental arsenic in this disease process are not known. Similarly, the impact of toxicants on blood vessel formation and function during development has not been studied. During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types including smooth muscle cells which contribute to the coronary vessels. The TGFβ family of ligands and receptors is essential for developmental cardiac epithelial to mesenchymal transition (EMT) and differentiation into coronary smooth muscle cells. In this in vitro study, 18hour exposure to 1.34μM arsenite disrupted developmental EMT programming in murine epicardial cells causing a deficit in cardiac mesenchyme. The expression of EMT genes including TGFβ2, TGFβ receptor-3, Snail, and Has-2 are decreased in a dose-dependent manner following exposure to arsenite. TGFβ2 cell signaling is abrogated as detected by decreases in phosphorylated Smad2/3 when cells are exposed to 1.34μM arsenite. There is also loss of nuclear accumulation pSmad due to arsenite exposure. These observations coincide with a decrease in vimentin positive mesenchymal cells invading three-dimensional collagen gels. However, arsenite does not block TGFβ2 mediated smooth muscle cell differentiation by epicardial cells. Overall these results show that arsenic exposure blocks developmental EMT gene programming in murine coronary progenitor cells by disrupting TGFβ2 signals and Smad activation, and that smooth muscle cell differentiation is refractory to this arsenic toxicity.
authors.affiliation: Department of Pharmacology and Toxicology College of Pharmacy, Southwest Environmental Health Sciences Center, Steele Children's Research Center and Bio5 Institute, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Allison
authors.forename: Tianfang
authors.initials: T
authors.lastname: Huang
authors.forename: Derrick
authors.initials: D
authors.lastname: Broka
authors.forename: Patti
authors.initials: P
authors.lastname: Parker
authors.forename: Joey V
authors.initials: JV
authors.lastname: Barnett
authors.forename: Todd D
authors.initials: TD
authors.lastname: Camenisch
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology* / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D007202:Indicators and Reagents; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D018053:Arsenites; D007202:Indicators and Reagents; D008840:Microfilament Proteins; D009124:Muscle Proteins; D051785:Smad Proteins; C058992:Tagln protein, mouse; D016212:Transforming Growth Factor beta; C015001:arsenite
keywords: Arsenic; Epicardial cells; Epithelial to mesenchymal transition; TGF-beta