title: CAMP-response element-binding protein mediates tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in endothelial cells.
abstract: Hypertension causes endothelial dysfunction, which plays an important role in atherogenesis. The vascular cell adhesion molecule-1 (VCAM-1) contributes to atherosclerotic lesion formation by recruiting leukocytes from blood into tissues. Tumor necrosis factor-alpha (TNFalpha) induces endothelial dysfunction and VCAM-1 expression in endothelial cells (ECs). We examined whether the cAMP-response element binding protein (CREB), a transcription factor that mediates cytokine expression and vascular remodeling, is involved in TNFalpha-induced VCAM-1 expression. TNFalpha induced phosphorylation of CREB with a peak at 15 min of stimulation in a dose-dependent manner in bovine aortic ECs. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38-MAPK) inhibited TNFalpha-induced CREB phosphorylation. Adenovirus-mediated overexpression of a dominant-negative form of CREB suppressed TNFalpha-induced VCAM-1 and c-fos expression. Although activating protein 1 DNA binding activity was attenuated by overexpression of dominant negative CREB, nuclear factor-kappaB activity was not affected. Our results suggest that the p38-MAPK/CREB pathway plays a critical role in TNFalpha-induced VCAM-1 expression in vascular endothelial cells. The p38MAPK/CREB pathway may be a novel therapeutic target for the treatment of atherosclerosis.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ono
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ichiki
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohtsubo
authors.forename: Kae
authors.initials: K
authors.lastname: Fukuyama
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Imayama
authors.forename: Naoko
authors.initials: N
authors.lastname: Iino
authors.forename: Satoko
authors.initials: S
authors.lastname: Masuda
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hashiguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002417:Cattle; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases