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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
07:49

Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling

Published on: August 3, 2018

c-Src and hydrogen peroxide mediate transforming growth factor-beta1-induced smooth muscle cell-gene expression in

Mahito Sato1, Keiko Kawai-Kowase, Hiroko Sato

  • 1Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Japan.

Arteriosclerosis, Thrombosis, and Vascular Biology
|December 14, 2004
PubMed
Abstract

Insights

Transforming growth factor-beta1 (TGF-beta1) signaling activates c-Src kinase and produces hydrogen peroxide, which are essential for regulating specific gene expression, including SM22alpha and PAI-1.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Gene regulation

Background:

  • Transforming growth factor-beta1 (TGF-beta1) is a key regulator of gene expression, influencing smooth muscle cell (SMC)-specific genes and extracellular matrix proteins.
  • The precise mechanisms by which TGF-beta1 exerts its regulatory effects are complex and involve multiple signaling cascades.

Purpose of the Study:

  • To investigate the role of the c-Src tyrosine kinase in TGF-beta1 signaling pathways.
  • To elucidate the involvement of hydrogen peroxide generation in TGF-beta1-mediated gene expression.

Main Methods:

  • Utilized mouse embryonic fibroblast C3H10T1/2 cells, including Src family tyrosine kinase-deficient SYF cells.
  • Employed pharmacological inhibitors (PP1, apocynin) and genetic manipulation (Csk) to modulate c-Src activity and NAD(P)H oxidase function.
  • Analyzed gene expression of SM22alpha and plasminogen activator inhibitor-1 (PAI-1) using quantitative methods.
  • Performed confocal immunofluorescence to detect hydrogen peroxide production.

Main Results:

  • TGF-beta1-induced expression of the SMC-specific gene SM22alpha was significantly reduced in c-Src-deficient cells and inhibited by PP1 and Csk.
  • TGF-beta1 treatment stimulated hydrogen peroxide production, and antioxidants/NAD(P)H oxidase inhibitors attenuated SM22alpha expression.
  • TGF-beta1 induction of PAI-1, a Smad-dependent gene, was also inhibited by PP1 and apocynin, suggesting a broader role for c-Src and hydrogen peroxide.

Conclusions:

  • TGF-beta1 signaling activates c-Src tyrosine kinase and promotes hydrogen peroxide generation via NAD(P)H oxidase.
  • These pathways are critical for the TGF-beta1-induced expression of specific genes, including SM22alpha and PAI-1.
  • c-Src and hydrogen peroxide are essential components of TGF-beta1 signaling for regulating target gene expression.

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