title: The expression of adhesion molecules on endothelial cells is inhibited by troglitazone through its antioxidant activity.
abstract: The adhesion of monocytes to endothelium, an early event in atherosclerosis, is mediated by cell adhesion molecules. Signal-transduction pathways for these binding molecules include the translocation of the transcription factor NF-kappaB; moreover, intracellularly generated oxygen-derived free radicals (ODFR) play a major role in this process. This study evaluated the extent to which troglitazone, an oral antidiabetic agent with antioxidant properties, affects the expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on human umbilical vein endothelial cells (HUVECs), induced by different prooxidant signals such as oxidized LDL and tumor necrosis factor-alpha (TNF-alpha). Furthermore we assessed whether the NF-kappaB activation is modulated by the antioxidative effect of troglitazone. Oxidized LDL not only caused a dose-dependent increase of ICAM-1, VCAM-1 and E-selectin (p<0.001), but also synergically increased their TNF-alpha-induced expression (p<0.001). Troglitazone reduced in a dose-dependent manner the expression of VCAM-1, ICAM-1 and E-selectin induced by different amounts of oxidized LDL (p<0.001). The addition of troglitazone to HUVECs significantly reduced the expression of ICAM-1, VCAM-1 and E-selectin induced by TNF-alpha alone or in combination with oxidized LDL (p<0.001); this reduction was paralleled by a significant fall in NF-kappaB translocation. The results suggest that troglitazone may have prevented NF-kappaB-mediated adhesion molecule expression by exerting its antioxidant effect on ODFR.
authors.affiliation: Istituto di Semeiotica e Nefrologia Medica, University of Verona, Ospedale Policlinico, Italy. comina@medicinad.univr.it
authors.forename: L
authors.initials: L
authors.lastname: Cominacini
authors.forename: U
authors.initials: U
authors.lastname: Garbin
authors.forename: A F
authors.initials: AF
authors.lastname: Pasini
authors.forename: A
authors.initials: A
authors.lastname: Davoli
authors.forename: M
authors.initials: M
authors.lastname: Campagnola
authors.forename: A
authors.initials: A
authors.lastname: Rigoni
authors.forename: L
authors.initials: L
authors.lastname: Tosetti
authors.forename: V
authors.initials: V
authors.lastname: Lo Cascio
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008077:Lipoproteins, LDL / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D015815:Cell Adhesion Molecules; D002839:Chromans; D019040:E-Selectin; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D013844:Thiazoles; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1; D014810:Vitamin E; D000077288:Troglitazone