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Tobacco smoke cooperates with interleukin-1ß to alter ß-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo

Silvia S. Barbieri^*, and Babette B. Weksler^*,1

^* Division of Hematology-Medical Oncology, Weill Medical College of Cornell University, New York, New York, USA; and

Department of Pharmacological Sciences, University of Milan, Milan, Italy

¹Correspondence: Division of Hematology-Medical Oncology, Weill Medical College of Cornell University, 1300 York Ave., 10021 New York, NY, USA. E-mail: babette{at}med.cornell.edu

Cigarette smoking affects all phases of atherosclerosis from endothelial dysfunction to acute occlusive clinical events. We explored activation by exposure to tobacco smoke of two genes, ß-catenin and COX-2, that play key roles in inflammation and vascular remodeling events. Using both in vivo and in vitro smoke exposure, we determined that tobacco smoke (TS) induced nuclear ß-catenin accumulation and COX-2 expression and activity and moreover interacted with IL-1ß to enhance these effects. Exposure of cardiac endothelial cells to tobacco smoke plus IL-1ß (TS/IL-1ß) enhanced permeability of endothelial monolayers and disrupted membrane VE-cadherin/ß-catenin complexes, decreased ß-catenin phosphorylation, and increased phosphorylation of GSK-3ß, Akt, and EGFR. Transfection of endothelial cells with ß-catenin-directed small interferring RNA (siRNA) suppressed TS/IL-1ß-mediated effects on COX-2 modulation. Inhibitors of EGFR and phosphatidylinositol-3-kinase also abolished both the TS/IL-1ß-mediated modulation of the Akt/GSK-3ß/ß-catenin pathway and enhancement of COX-2 expression. Moreover, increased levels of Akt and GSK-3ß phosphorylation, nuclear ß-catenin accumulation, COX-2 expression, and IL-1ß were observed in cardiovascular tissue of ApoE^–/– mice exposed to cigarette smoke daily for 2 wk. Our results suggest a novel mechanism by which cigarette smoking can induce proinflammatory and proatherosclerotic effects in vascular tissue.—Barbieri, S. S., Weksler, B. B. Tobacco smoke cooperates with interleukin-1ß to alter ß-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo.

Key Words: endothelial cells • inflammation • signal transduction

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				S. S. Barbieri, L. Ruggiero, E. Tremoli, and B. B. Weksler Suppressing PTEN Activity by Tobacco Smoke Plus Interleukin-1{beta} Modulates Dissociation of VE-Cadherin/{beta}-Catenin Complexes in Endothelium Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 732 - 738. [Abstract] [Full Text] [PDF]