The expression of adhesion molecules on endothelial cells is inhibited by troglitazone through its antioxidant activity.
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.
Cominacini
L
L
Istituto di Semeiotica e Nefrologia Medica, University of Verona, Ospedale Policlinico, Italy. comina@medicinad.univr.it
Garbin
U
U
Pasini
A F
AF
Davoli
A
A
Campagnola
M
M
Rigoni
A
A
Tosetti
L
L
Lo Cascio
V
V
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
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