Arsenite disrupts zinc-dependent TGFβ2-SMAD activity during murine cardiac progenitor cell differentiation

Tianfang Huang, Eric J. Ditzel, Alec B. Perrera, Derrick M. Broka, Todd D Camenisch

Research output: Contribution to journalArticle

Abstract

TGFβ2 (transforming growth factor-β2) is a key growth factor regulating epithelial to mesenchymal transition (EMT). TGFβ2 triggers cardiac progenitor cells to differentiate into mesenchymal cells and give rise to the cellular components of coronary vessels as well as cells of aortic and pulmonary valves. TGFβ signaling is dependent on a dynamic on and off switch in Smad activity. Arsenite exposure of 1.34 μM for 24-48 h has been reported to disrupt Smad phosphorylation leading to deficits in TGFβ2-mediated cardiac precursor differentiation and transformation. In this study, the molecular mechanism of acute arsenite toxicity on TGFβ2-induced Smad2/3 nuclear shuttling and TGFβ2-mediated cardiac EMT was investigated. A 4-h exposure to 5 μM arsenite blocks nuclear accumulation of Smad2/3 in response to TGFβ2 without disrupting Smad phosphorylation or nuclear importation. The depletion of nuclear Smad is restored by knocking-down Smad-specific exportins, suggesting that arsenite augments Smad2/3 nuclear exportation. The blockage in TGFβ2-Smad signaling is likely due to the loss of Zn2+ cofactor in Smad proteins, as Zn2+ supplementation reverses the disruption in Smad2/3 nuclear translocation and transcriptional activity by arsenite. This coincides with Zn2+ supplementation rescuing arsenite-mediated deficits in cardiac EMT. Thus, zinc partially protects cardiac EMT from developmental toxicity by arsenite.

Original languageEnglish (US)
Article numberkfv191
Pages (from-to)409-420
Number of pages12
JournalToxicological Sciences
Volume148
Issue number2
DOIs
StatePublished - Dec 1 2015

Fingerprint

Transforming Growth Factors
Zinc
Cell Differentiation
Stem Cells
Epithelial-Mesenchymal Transition
Phosphorylation
Toxicity
Smad Proteins
Karyopherins
Pulmonary Valve
arsenite
Aortic Valve
Intercellular Signaling Peptides and Proteins
Coronary Vessels
Switches

Keywords

  • Arsenite
  • Cardiac EMT
  • TGFβ-Smad signaling
  • Zinc

ASJC Scopus subject areas

  • Toxicology

Cite this

Arsenite disrupts zinc-dependent TGFβ2-SMAD activity during murine cardiac progenitor cell differentiation. / Huang, Tianfang; Ditzel, Eric J.; Perrera, Alec B.; Broka, Derrick M.; Camenisch, Todd D.

In: Toxicological Sciences, Vol. 148, No. 2, kfv191, 01.12.2015, p. 409-420.

Research output: Contribution to journalArticle

Huang, Tianfang ; Ditzel, Eric J. ; Perrera, Alec B. ; Broka, Derrick M. ; Camenisch, Todd D. / Arsenite disrupts zinc-dependent TGFβ2-SMAD activity during murine cardiac progenitor cell differentiation. In: Toxicological Sciences. 2015 ; Vol. 148, No. 2. pp. 409-420.
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