Insulin potentiates cytokine-induced VCAM-1 expression in human endothelial cells.
Hyperinsulinemia is an independent risk factor for cardiovascular events and may contribute to cardiovascular disease. Low-grade chronic inflammation has been implicated in the pathogenesis of atherosclerosis. We aimed at determining the impact of pathophysiologically high insulin concentrations on cytokine-induced endothelial activation in human umbilical vein endothelial cells (HUVEC). HUVEC were incubated with insulin (0-24 h)+/-tumor necrosis factor (TNF)-alpha or lipopolysaccharide (LPS). At pathophysiological/pharmacological concentrations (10(-9)-10(-7) mol/L), insulin selectively induced VCAM-1 expression and potentiated the effects of TNF-alpha andLPS, effects reverted by the proteasome inhibitor lactacystin. Compared with TNF-alpha alone, insulin+TNF-alpha doubled U937 cell adhesion. Insulin markedly increased TNF-alpha-induced NF-kappaB activation and induced phosphorylated IkappaB-alpha accumulation. Therefore, hyperinsulinemia enhances cytokine-induced VCAM-1 expression in endothelial cells, thus potentially contributing to detrimental effects of other inflammatory stimuli on atherogenesis.
Madonna
Rosalinda
R
Institute of Cardiology, Center of Excellence on Aging, G. d'Annunzio University-Chieti, Italy.
Massaro
Marika
M
De Caterina
Raffaele
R
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D015152:Blotting, Northern; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells; D014470:Umbilical Cord / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D020672:I-kappa B Proteins; D007328:Insulin; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C067713:lactacystin; D000072000:NF-KappaB Inhibitor alpha; D000111:Acetylcysteine