Insulin levels are a marker for cardiovascular events, but the link between hyperinsulinemia and atherosclerosis is poorly understood. We previously showed that insulin increases monocyte-endothelial interactions and the endothelial expression of the pro-atherogenic vascular cell adhesion molecule-1 (VCAM-1). The aim of this study is to examine molecular mechanisms involved in the effect of insulin on VCAM-1 expression. Human umbilical vein endothelial cells (HUVEC) were incubated with insulin (0-24 h) +/- inhibitors of signaling pathways potentially involved. At path ophysiological concentrations (10(-9)-10(-7) M), insulin selectively induced VCAM-1 expression. The p38mitogen activated protein(MAP) kinase inhibitors SB203580 and SB202190, and partially the c-Jun NH2-terminal kinase (JNK) inhibitor SP600127, decreased insulin effect on VCAM-1. Gene silencing by small interfering RNA significantly reduced the expression of p38MAPkinase, and this was accompanied by suppression of insulin-stimulated VCAM-1 expression. Treatment with insulin also led to the activation of NF-kappa B and induction of IKB-alpha phosphorylation, thus accounting for NF-kappa B translocation into the nucleus. Co-treatment of HUVEC with insulin and SB202190 strongly reverted the stimulatory effect of insulin on NF-kappa B activation, thus establishing a link between NF-kappa B activation and p38MAPkinase-mediated induction of VCAM-1 by insulin. In conclusion, pathophysiological insulin concentrations increase VCAM-1 expression and activate NF-kappa B. This mostly occurs through stimulation of p38MAP kinase.
The prominent role of p38 mitogen-activated protein kinase in insulin-mediated enhancement of VCAM-1 expression in endothelial cells / Madonna, R; Massaro, M; Pandolfi, A; Consoli, A; DE CATERINA, R.. - In: INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY. - ISSN 0394-6320. - STAMPA. - 20:3(2007), pp. 539-555.
|Autori:||Madonna, R; Massaro, M; Pandolfi, A; Consoli, A; DE CATERINA, R.|
|Titolo:||The prominent role of p38 mitogen-activated protein kinase in insulin-mediated enhancement of VCAM-1 expression in endothelial cells|
|Anno del prodotto:||2007|
|Appare nelle tipologie:||1.1 Articolo in rivista|