The Prominent Role of P38 Mitogen-Activated Protein Kinase in Insulin-Mediated Enhancement of VCAM-1 Expression in Endothelial Cells

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 pathophysiological 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 p38MAP kinase, and this was accompanied by suppression of insulin-stimulated VCAM-1 expression. Treatment with insulin also led to the activation of NF-κB and induction of IκB-α phosphorylation, thus accounting for NF-κB translocation into the nucleus. Co-treatment of HUVEC with insulin and SB202190 strongly reverted the stimulatory effect of insulin on NF-κB activation, thus establishing a link between NF-κB activation and p38MAPkinase-mediated induction of VCAM-1 by insulin. In conclusion, pathophysiological insulin concentrations increase VCAM-1 expression and activate NF-κB. This mostly occurs through stimulation of p38MAP kinase.