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Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications
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Aryl hydrocarbon receptor ligands repress T-cadherin expression in vascular smooth muscle cells

Thomas Niermann1, Sanja Schmutz, Paul Erne

  • 1Department of Research, Cardiovascular Laboratories, ZLF 320, Basel University Hospital, Hebelstrasse 20, CH 4031 Basel, Switzerland.

Biochemical and Biophysical Research Communications
|February 1, 2003
PubMed

Insights

T-cadherin, a cardiac and vascular protein, is negatively regulated by the aryl hydrocarbon receptor (AhR) signaling pathway. This suggests a new mechanism for how polycyclic aromatic hydrocarbons impact cardiovascular health.

Area of Science:

  • Cardiovascular Biology
  • Molecular Toxicology
  • Gene Regulation

Background:

  • T-cadherin is highly expressed in cardiac and vascular tissues, but its functions and regulation remain unclear.
  • The 5' untranslated regions of T-cadherin genes contain a conserved motif similar to dioxin-responsive elements, suggesting a potential link to the aryl hydrocarbon receptor (AhR) pathway.

Purpose of the Study:

  • To investigate the regulation of T-cadherin expression in vascular cells.
  • To determine if T-cadherin is a target gene for the AhR signaling pathway.

Main Methods:

  • Cloning of rat T-cadherin cDNA.
  • Treatment of rat aortic smooth muscle cells with AhR agonists (benzo[a]pyrene, 7,12-dimethylbenzanthracene, TCDD) and an antagonist (alpha-naphthoflavone).
  • Analysis of T-cadherin mRNA levels and effects of transcription/translation inhibitors (actinomycin D, cycloheximide).

Main Results:

  • AhR agonists significantly repressed T-cadherin mRNA levels in a dose-dependent manner.
  • The repressive effect was blocked by the AhR antagonist alpha-naphthoflavone.
  • Repression occurred independently of de novo protein synthesis or gene transcription, indicating direct transcriptional regulation by AhR/ARNT.

Conclusions:

  • T-cadherin is a novel target gene negatively regulated by AhR signaling in vascular smooth muscle cells.
  • AhR-mediated regulation of adhesion proteins like T-cadherin may represent a new mechanism for the atherogenic effects of polycyclic aromatic hydrocarbons.
  • This finding sheds light on the molecular mechanisms linking environmental pollutants to cardiovascular disease.

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