title: Thrombin, TNF-alpha, and LPS exert overlapping but nonidentical effects on gene expression in endothelial cells and vascular smooth muscle cells.
abstract: Thrombin, TNF-alpha, and LPS have each been implicated in endothelial cell and vascular smooth muscle cell (VSMC) activation. We wanted to test the hypothesis that these three agonists display mediator and/or cell type-specific properties. The addition of thrombin to human pulmonary artery endothelial cells resulted in an upregulation of PDGF-A, tissue factor (TF), ICAM-1, and urokinase-type plasminogen activator (u-PA), whereas TNF-alpha and LPS failed to induce PDGF-A. These effects were mimicked by protease-activated receptor-1 activation. In VSMC, thrombin induced expression of TF and PDGF-A but failed to consistently induce ICAM-1 or u-PA expression. In contrast, TNF-alpha and LPS increased expression of all four genes in this cell type. Inhibitor studies in endothelial cells demonstrated a critical role for PKC in mediating thrombin, TNF-alpha, and LPS induction of ICAM-1, TF, and u-PA and for p38 MAPK in mediating thrombin, TNF-alpha, and LPS induction of TF. Taken together, these results suggest that inflammatory mediators engage distinct signaling pathways and expression profiles in endothelial cells and VSMC. The data support the notion that endothelial cell activation is not an all-or-nothing phenomenon but rather is dependent on the nature of the extracellular mediator.
authors.affiliation: Division of Molecular and Vascular Medicine, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, RW-663, 330 Brookline Ave., Boston, MA 02215, USA.
authors.forename: Sheng-Qian
authors.initials: SQ
authors.lastname: Wu
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C075278:platelet-derived growth factor A; D018799:Intercellular Adhesion Molecule-1; D013925:Thromboplastin; D013917:Thrombin; D014568:Urokinase-Type Plasminogen Activator