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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:732.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

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

From the Department of Pharmacological Sciences (S.S.B., E.T.), University of Milan, Italy; the Division of Hematology-Medical Oncology (S.S.B., B.B.W.), Weill Medical College of Cornell University, New York; and the Monzino Cardiologic Center I.R.C.C.S (L.R., E.T.), Milan, Italy.

Correspondence to Babette B. Weksler, MD, Division of Hematology-Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065. E-mail babette{at}med.cornell.edu

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.

Tobacco smoke (TS) cooperates with interleukin-1β to accelerate and enhance endothelial dysfunction. Our study shows that PTEN deactivation induced by TS plus IL-1β modulates tyrosine phosphorylation and destabilizes VE-cadherin/β-catenin complexes. Therefore, pharmacological inhibitors of PTEN-deactivation may represent potential therapeutic tools to prevent endothelial-related vascular disorders.

Key Words: smoke • PTEN • tyrosine phosphorylation • VE-cadherin • β-catenin