This Article Full Text Full Text (PDF) Additional Materials All Versions of this Article: 28/4/732    most recent ATVBAHA.107.159434v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barbieri, S. S. Articles by Weksler, B. B. Search for Related Content PubMed PubMed Citation Articles by Barbieri, S. S. Articles by Weksler, B. B. Related Collections Animal models of human disease Pathophysiology Risk Factors Cell signalling/signal transduction Physiological and pathological control of gene expression Mechanism of atherosclerosis/growth factors

(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

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

This article has been cited by other articles:

				J. W. Kim, K. H. Kang, P. Burrola, T. W. Mak, and G. Lemke Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium Genes & Dev., November 15, 2008; 22(22): 3147 - 3157. [Abstract] [Full Text] [PDF]