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• W2550881470 abstract "Abstract While cigarette smoking is a major risk factor for atherosclerosis and for acute cardiovascular events, the toxic components of tobacco smoke (TS) and mechanisms producing cardiovascular dysfunction are unknown. Exposure to TS increases inflammation, thrombosis, and oxidation of LDL cholesterol and we have previously found that TS exposure activates several inflammatory genes in vascular cells. To address the mechanisms of TS-induced proatherosclerotic effects, we derived an immortalized line of mouse cardiac microvascular endothelial (MMCEC) cells by transfection of primary cells with lentiviral vectors encoding genes for telomerase and SV40 T antigen. These MMCEC grow indefinitely while retaining a normal endothelial phenotype, show contact inhibition, display EC markers such as PECAM, VE-cadherin, and von Willebrand factor, and develop an inflammatory phenotype when stimulated with cytokines. In response to interleukin-1β (IL-1 β), MMCEC induce cyclooxygenase-2 (COX-2) and produce prostaglandins; these effects are enhanced by a saline extract of TS in a dose- and time-dependent manner. Increased COX-2 expression accompanies atherosclerosis, while its prostaglandin products favor cell proliferation and decrease apoptosis. Moreover, β-catenin, a key component of cell-cell interactions, and a coactivator of the TCF/LEF (T-cell transcription factor/lymphoid enhancer binding factor) family of transcription factors, is also increased in atherosclerotic plaques. We therefore studied how TS exposure affected the Wnt/β-catenin pathway. IL-1 β and TS each stimulated β-catenin translocation from the plasma membrane to the nucleus of MMCEC within 1–2 hr, but addition of TS to cells exposed to IL-1 β stimulated translocation within minutes shown by confocal microscopy and western blotting. The enhanced β-catenin translocation induced by IL-1 β/TS was linked with rapid phosphorylation of Akt and glycogen synthase kinase 3β, which in turn decreased phosphorylation of β-catenin, preventing its proteosomal degradation. Conversely, when GSK3β, which stabilizes β-catenin, was blocked, COX-2 was induced. If β-catenin expression in MMCEC was directly inhibited by transfection of cells with short interfering RNA (siRNA) induction of COX-2 expression and prostaglandin production by IL-1 β/TS was markedly diminished. In addition, LY294002, an inhibitor of phosphatidylinositol-3-kinase, and AG1478, an EGFR inhibitor, also blocked IL-1 β/TS induced Akt phosphorylation, β-catenin translocation and COX-2 expression, as did selective inhibitors of p38 MAPK and MEK-1. Our data, using a novel endothelial cell model, demonstrate that the PI3K/GSK-3β regulated β-catenin pathway is important for COX-2-related proinflammatory and proatherosclerotic effects of tobacco smoke on vascular cells and indicate the interrelated signaling pathways involved. TS-related effects may similarly modulate other proatherosclerotic genes." @default.
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• W2550881470 date "2005-11-16" @default.
• W2550881470 modified "2023-09-30" @default.
• W2550881470 title "Rapid Wnt/β-Catenin Pathway Activation by Tobacco Smoke Modulates Cyclooxygenase-2 Expression in Cardiac Microvascular Endothelial Cells." @default.
• W2550881470 doi "https://doi.org/10.1182/blood.v106.11.3697.3697" @default.
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