Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 28, Issue 4, Pages 732-738Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.107.159434
Keywords
smoke; PTEN; tyrosine phosphorylation; VE-cadherin; beta-catenin
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Funding
- NHLBI NIH HHS [R0-1 HL55627] Funding Source: Medline
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Objectives - Tobacco smoke (TS) interacts with inflammatory cytokines to produce endothelial dysfunction. We hypothesized that interleukin-1 beta (IL-1 beta) plus TS (TS/IL-1 beta) induces disassembly of endothelial junctional complexes of VE-cadherin/beta-catenin by suppression of PTEN activity and investigated molecular mechanisms that modulate PTEN-deactivation in this situation. Methods and Results - TS/IL-1 beta exposure, which disrupted adherens junctions and induced nuclear beta-catenin accumulation, increased tyrosine phosphorylation (p-Tyr) of VE-cadherin and beta-catenin, and reduced PTEN activity. Overexpression or silencing of PTEN modulated p-Tyr of both VE-cadherin and beta-catenin, changed assembly of adherens junction complexes, and altered nuclear beta-catenin accumulation. In addition, inhibiting ROS production stimulated by TS/IL-1 beta decreased activation of Src, EGFR and p38MAPK, phosphorylation of PTEN, VE-cadherin and beta-catenin, and abrogated the effect of TS/IL-1 beta to disorganize adherens junctions, resulting in reduced endothelial permeability and decreased nuclear beta-catenin accumulation. Finally, exposure of ApoE(-/-) mice to cigarette smoke induced phosphorylation of Src, EGFR, p-38MAPK, PTEN, and beta-catenin, and disrupted VE-cadherin/beta-catenin complexes in cardiovascular tissue. Conclusions - TS interaction with IL-1 beta modulates PTEN activity though the ROS/Src/EGFR-p38MAPK pathway. PTEN deactivation is essential to increase VE- cadherin and beta-catenin p-Tyr and to disassemble VE-cadherin/ beta-catenin membrane complexes, events that lead to accumulation of beta-catenin within the nucleus.
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