Suppressing PTEN activity by tobacco smoke plus interleukin-1β modulates dissociation of VE-cadherin/β-catenin complexes in endothelium

Silvia S. Barbieri, Luca Ruggiero, Elena Tremoli, Babette B. Weksler

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish
Pages (from-to)732-738
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number4
DOIs
Publication statusPublished - Apr 2008

Keywords

  • β-catenin
  • PTEN
  • Smoke
  • Tyrosine phosphorylation
  • VE-cadherin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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