Aryl hydrocarbon receptor ligands repress T-cadherin expression in vascular smooth muscle cells.

T-cadherin, a glycosylphosphatidylinositol-modified cadherin subtype, is highly expressed in cardiac and vascular tissues. Neither the functions nor regulation of T-cadherin in these tissues is understood. We have cloned rat T-cadherin cDNA encoding the full length amino acid sequence. The 5(') untranslated nucleotide sequences of rat, mouse, and human T-cadherin contain a conserved GCGTG motif which constitutes the invariant core sequence of dioxin- or xenobiotic-regulatory elements. These elements function as target sites for aryl hydrocarbon receptor/aryl hydrocarbon nuclear translocator (AhR/ARNT) in genes regulated by this transcription factor. Using cultures of rat aortic smooth muscle cells this study presents data revealing T-cadherin as a putative target gene for negative regulation of expression through AHR signalling. Prototypic AHR agonists benzo[a]pyrene (BaP) or 7,12-dimethylbenzanthracene (DMBA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) repressed T-cadherin mRNA levels. Repression was antagonized by the cognate AHR antagonist alpha-naphthoflavone (alpha-NF). Repression was insensitive to inhibitors of gene transcription (actinomycin D) or de novo protein synthesis (cycloheximide), suggesting AHR/ARNT functions directly in transcriptional repression of T-cad. Regulation of adhesion proteins through the AHR pathway may represent a novel mechanism of action by atherogenic polycyclic aromatic hydrocarbons.