Disruption of canonical TGFβ-signaling in murine coronary progenitor cells by low level arsenic

Patrick Allison, Tianfang Huang, Derrick Broka, Patti Parker, Joey V. Barnett, Todd D Camenisch

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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, 18. hour exposure to 1.34. μM 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 1.34. μM 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.

Original languageEnglish (US)
Pages (from-to)147-153
Number of pages7
JournalToxicology and Applied Pharmacology
Volume272
Issue number1
DOIs
Publication statusPublished - Oct 1 2013

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Keywords

  • Arsenic
  • Epicardial cells
  • Epithelial to mesenchymal transition
  • TGF-beta

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Disruption of canonical TGFβ-signaling in murine coronary progenitor cells by low level arsenic. / Allison, Patrick; Huang, Tianfang; Broka, Derrick; Parker, Patti; Barnett, Joey V.; Camenisch, Todd D.

In: Toxicology and Applied Pharmacology, Vol. 272, No. 1, 01.10.2013, p. 147-153.

Research output: Contribution to journalArticle