CAMP-response element-binding protein mediates tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in endothelial cells

Hypertens Res. 2006 Jan;29(1):39-47. doi: 10.1291/hypres.29.39.

Abstract

Hypertension causes endothelial dysfunction, which plays an important role in atherogenesis. The vascular cell adhesion molecule-1 (VCAM-1) contributes to atherosclerotic lesion formation by recruiting leukocytes from blood into tissues. Tumor necrosis factor-alpha (TNFalpha) induces endothelial dysfunction and VCAM-1 expression in endothelial cells (ECs). We examined whether the cAMP-response element binding protein (CREB), a transcription factor that mediates cytokine expression and vascular remodeling, is involved in TNFalpha-induced VCAM-1 expression. TNFalpha induced phosphorylation of CREB with a peak at 15 min of stimulation in a dose-dependent manner in bovine aortic ECs. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38-MAPK) inhibited TNFalpha-induced CREB phosphorylation. Adenovirus-mediated overexpression of a dominant-negative form of CREB suppressed TNFalpha-induced VCAM-1 and c-fos expression. Although activating protein 1 DNA binding activity was attenuated by overexpression of dominant negative CREB, nuclear factor-kappaB activity was not affected. Our results suggest that the p38-MAPK/CREB pathway plays a critical role in TNFalpha-induced VCAM-1 expression in vascular endothelial cells. The p38MAPK/CREB pathway may be a novel therapeutic target for the treatment of atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Cattle
  • Cell Nucleus / chemistry
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • Electrophoretic Mobility Shift Assay
  • Endothelial Cells / metabolism*
  • Genetic Vectors / genetics
  • Phosphorylation
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vascular Cell Adhesion Molecule-1 / biosynthesis*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • p38 Mitogen-Activated Protein Kinases