title: Tobacco smoke cooperates with interleukin-1beta to alter beta-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo.
abstract: 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, beta-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 beta-catenin accumulation and COX-2 expression and activity and moreover interacted with IL-1beta to enhance these effects. Exposure of cardiac endothelial cells to tobacco smoke plus IL-1beta (TS/IL-1beta) enhanced permeability of endothelial monolayers and disrupted membrane VE-cadherin/beta-catenin complexes, decreased beta-catenin phosphorylation, and increased phosphorylation of GSK-3beta, Akt, and EGFR. Transfection of endothelial cells with beta-catenin-directed small interfering RNA (siRNA) suppressed TS/IL-1beta-mediated effects on COX-2 modulation. Inhibitors of EGFR and phosphatidylinositol-3-kinase also abolished both the TS/IL-1beta-mediated modulation of the Akt/GSK-3beta/beta-catenin pathway and enhancement of COX-2 expression. Moreover, increased levels of Akt and GSK-3beta phosphorylation, nuclear beta-catenin accumulation, COX-2 expression, and IL-1beta 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.
authors.affiliation: Division of Hematology-Medical Oncology, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021, USA.
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Barbieri
authors.forename: Babette B
authors.initials: BB
authors.lastname: Weksler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D050197:Atherosclerosis; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000502:physiology*; D051379:Mice; D009206:Myocardium / Q000166:cytology; D010539:Permeability; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D014026:Nicotiana
chemical_list: D053583:Interleukin-1beta; D012906:Smoke; D051176:beta Catenin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2