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

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 (TNF alpha) 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 TNF alpha-induced VCAM-1 expression. TNF alpha 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 TNF alpha-induced CREB phosphorylation. Adenovirus-mediated overexpression of a dominant-negative form of CREB suppressed TNF alpha-induced VCAM-1 and c-fos expression. Although activating protein I DNA binding activity was attenuated by overexpression of dominant negative CREB, nuclear factor-kappa B activity was not affected. Our results suggest that the p38-MAPK/CREB pathway plays a critical role in TNFa-induced VCAM-1 expression in vascular endothelial cells. The p38-MAPK/CREB pathway may be a novel therapeutic target for the treatment of atherosclerosis.