Cardiac epithelial-mesenchymal transition is blocked by monomethylarsonous acid (III)

Tianfang Huang, Joey V. Barnett, Todd D Camenisch

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 (iAsIII) 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.

Original languageEnglish (US)
Pages (from-to)225-238
Number of pages14
JournalToxicological Sciences
Volume142
Issue number1
DOIs
StatePublished - Nov 1 2014

Fingerprint

Epithelial-Mesenchymal Transition
Arsenic
Arsenicals
Coronary Vessels
Stem Cells
Chemical activation
monomethylarsonous acid
Phosphorylation
Poisons
Blood vessels
Pathology
Cytotoxicity
Metabolites
arsenite
Refractory materials
Embryonic Development
Smooth Muscle
Blood Vessels
Toxicity
Muscle

Keywords

  • Arsenicals
  • Cardiovascular development
  • MMA (III)
  • TGFβ

ASJC Scopus subject areas

  • Toxicology

Cite this

Cardiac epithelial-mesenchymal transition is blocked by monomethylarsonous acid (III). / Huang, Tianfang; Barnett, Joey V.; Camenisch, Todd D.

In: Toxicological Sciences, Vol. 142, No. 1, 01.11.2014, p. 225-238.

Research output: Contribution to journalArticle

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