Suppressing PTEN Activity by Tobacco Smoke Plus Interleukin-1β Modulates Dissociation of VE-Cadherin/β-Catenin Complexes in Endothelium

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.