Suppressing PTEN activity by tobacco smoke plus interleukin-1beta modulates dissociation of VE-cadherin/beta-catenin complexes in endothelium. Academic Article uri icon

Overview

abstract

  • OBJECTIVE: Tobacco smoke (TS) interacts with inflammatory cytokines to produce endothelial dysfunction. We hypothesized that interleukin-1beta (IL-1beta) plus TS (TS/IL-1beta) induces disassembly of endothelial junctional complexes of VE-cadherin/beta-catenin by suppression of PTEN activity and investigated molecular mechanisms that modulate PTEN-deactivation in this situation. METHODS AND RESULTS: TS/IL-1beta exposure, which disrupted adherens junctions and induced nuclear beta-catenin accumulation, increased tyrosine phosphorylation (p-Tyr) of VE-cadherin and beta-catenin, and reduced PTEN activity. Overexpression or silencing of PTEN modulated p-Tyr of both VE-cadherin and beta-catenin, changed assembly of adherens junction complexes, and altered nuclear beta-catenin accumulation. In addition, inhibiting ROS production stimulated by TS/IL-1beta decreased activation of Src, EGFR and p38MAPK, phosphorylation of PTEN, VE-cadherin and beta-catenin, and abrogated the effect of TS/IL-1beta to disorganize adherens junctions, resulting in reduced endothelial permeability and decreased nuclear beta-catenin accumulation. Finally, exposure of ApoE(-/-) mice to cigarette smoke-induced phosphorylation of Src, EGFR, p-38MAPK, PTEN, and beta-catenin, and disrupted VE-cadherin/beta-catenin complexes in cardiovascular tissue. CONCLUSIONS: TS interaction with IL-1beta modulates PTEN activity though the ROS/Src/EGFR-p38MAPK pathway. PTEN deactivation is essential to increase VE-cadherin and beta-catenin p-Tyr and to disassemble VE-cadherin/beta-catenin membrane complexes, events that lead to accumulation of beta-catenin within the nucleus.

publication date

  • January 17, 2008

Research

keywords

  • Antigens, CD
  • Cadherins
  • Endothelium, Vascular
  • Interleukin-1beta
  • Nicotiana
  • PTEN Phosphohydrolase
  • Smoke
  • Tobacco
  • beta Catenin

Identity

Scopus Document Identifier

  • 42249110548

Digital Object Identifier (DOI)

  • 10.1161/ATVBAHA.107.159434

PubMed ID

  • 18202321

Additional Document Info

volume

  • 28

issue

  • 4