title: Cardiac epithelial-mesenchymal transition is blocked by monomethylarsonous acid (III).
abstract: Arsenic exposure during embryonic development can cause ischemic heart pathologies later in adulthood which may originate from impairment in proper blood vessel formation. The arsenic-associated detrimental effects are mediated by arsenite (iAs(III)) and its most toxic metabolite, monomethylarsonous acid [MMA (III)]. The impact of MMA (III) on coronary artery development has not yet been studied. The key cellular process that regulates coronary vessel development is the epithelial-mesenchymal transition (EMT). During cardiac EMT, activated epicardial progenitor cells transform to mesenchymal cells to form the cellular components of coronary vessels. Smad2/3 mediated TGFβ2 signaling, the key regulator of cardiac EMT, is disrupted by arsenite exposure. In this study, we compared the cardiac toxicity of MMA (III) with arsenite. Epicardial progenitor cells are 15 times more sensitive to MMA (III) cytotoxicity when compared with arsenite. MMA (III) caused a significant blockage in epicardial cellular transformation and invasion at doses 10 times lower than arsenite. Key EMT genes including TGFβ ligands, TβRIII, Has2, CD44, Snail1, TBX18, and MMP2 were down regulated by MMA (III) exposure. MMA (III) disrupted Smad2/3 activation at a dose 20 times lower than arsenite. Both arsenite and MMA (III) significantly inhibited Erk1/2 and Erk5 phosphorylation. Nuclear translocation of Smad2/3 and Erk5 was also blocked by arsenical exposure. However, p38 activation, as well as smooth muscle differentiation, was refractory to the inhibition by the arsenicals. Collectively, these findings revealed that MMA (III) is a selective disruptor of cardiac EMT and as such may predispose to arsenic-associated cardiovascular disorders.
authors.affiliation: Department of Pharmacology and Toxicology College of Pharmacy, University of Arizona, Tucson, Arizona 85721 camenisch@pharmacy.arizona.edu.
authors.forename: Tianfang
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
authors.forename: Joey V
authors.initials: JV
authors.lastname: Barnett
authors.affiliation: Department of Pharmacology and Toxicology College of Pharmacy, University of Arizona, Tucson, Arizona 85721 Southwest Environmental Health Sciences Center, University of Arizona, Tucson, Arizona 85721 Steele Children's Research Center, University of Arizona, Tucson, Arizona 85724 Sarver Heart Center Bio5 Institute, University of Arizona, Tucson, Arizona 85721.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Camenisch
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008822:Mice, Transgenic; D038081:Organogenesis / Q000187:drug effects / Q000235:genetics; D009942:Organometallic Compounds / Q000633:toxicity*; D010496:Pericardium / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D018053:Arsenites; D009942:Organometallic Compounds; C406082:monomethylarsonous acid; C015001:arsenite
keywords: MMA (III); TGFβ; arsenicals; cardiovascular development