on January 17, 2008
Published online before print January 17, 2008, doi: 10.1161/ATVBAHA.107.159434
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on August 8, 2007
Accepted on January 3, 2008
Suppressing PTEN Activity by Tobacco Smoke Plus Interleukin-1
Modulates Dissociation of VE-Cadherin/-Catenin Complexes in Endothelium
Silvia S. Barbieri ;
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.
* To whom correspondence should be addressed. E-mail: babette{at}med.cornell.edu.
Objectives—Tobacco smoke (TS) interacts with inflammatory cytokines to produce endothelial dysfunction. We hypothesized that interleukin-1
(IL-1) plus TS (TS/IL-1) induces disassembly of endothelial junctional complexes of VE-cadherin/-catenin by suppression of PTEN activity and investigated molecular mechanisms that modulate PTEN-deactivation in this situation.
Methods and Results—TS/IL-1 exposure, which disrupted adherens junctions and induced nuclear -catenin accumulation, increased tyrosine phosphorylation (p-Tyr) of VE-cadherin and -catenin, and reduced PTEN activity. Overexpression or silencing of PTEN modulated p-Tyr of both VE-cadherin and -catenin, changed assembly of adherens junction complexes, and altered nuclear -catenin accumulation. In addition, inhibiting ROS production stimulated by TS/IL-1, decreased activation of Src, EGFR and p38MAPK, phosphorylation of PTEN, VE-cadherin and -catenin, and abrogated the effect of TS/IL-1 to disorganize adherens junctions, resulting in reduced endothelial permeability and decreased nuclear -catenin accumulation. Finally, exposure of ApoE-/- mice to cigarette smoke–induced phosphorylation of Src, EGFR, p-38MAPK, PTEN, and -catenin, and disrupted VE-cadherin/-catenin complexes in cardiovascular tissue.
Conclusions—TS interaction with IL-1 modulates PTEN activity though the ROS/Src/EGFR-p38MAPK pathway. PTEN deactivation is essential to increase VE-cadherin and -catenin p-Tyr and to disassemble VE-cadherin/-catenin membrane complexes, events that lead to accumulation of -catenin within the nucleus.
Key words: smoke • PTEN • tyrosine phosphorylation • VE-cadherin •
-catenin