The prominent role of p38 mitogen-activated protein kinase in insulin-mediated enhancement of VCAM-1 expression in endothelial cells

Int J Immunopathol Pharmacol. 2007 Jul-Sep;20(3):539-55. doi: 10.1177/039463200702000312.


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 p38 mitogen 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-KB and induction of IKB-alpha phosphorylation, thus accounting for NF-KB translocation into the nucleus. Co-treatment of HUVEC with insulin and SB202190 strongly reverted the stimulatory effect of insulin on NF-KB activation, thus establishing a link between NF-KB activation and p38MAPkinase-mediated induction of VCAM-1 by insulin. In conclusion, pathophysiological insulin concentrations increase VCAM-1 expression and activate NF-KB. This mostly occurs through stimulation of p38MAP kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Electrophoretic Mobility Shift Assay
  • Endothelial Cells* / drug effects
  • Endothelial Cells* / enzymology
  • Endothelial Cells* / metabolism
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • I-kappa B Proteins / metabolism
  • Immunoblotting
  • Immunohistochemistry
  • Insulin / pharmacology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Phosphorylation
  • Transfection
  • Up-Regulation
  • Vascular Cell Adhesion Molecule-1 / biosynthesis*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / physiology*


  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • I-kappa B Proteins
  • Insulin
  • NF-kappa B
  • NFKBIA protein, human
  • Vascular Cell Adhesion Molecule-1
  • NF-KappaB Inhibitor alpha
  • p38 Mitogen-Activated Protein Kinases