Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappa B activation induced by intracellular oxidative stress

The recruitment of monocytes via the endothelial expression of vascular cel l adhesion molecule-1 (VCAM-1) is a key step in the formation of the initia l lesion in atherosclerosis. Because angiotensin (Ang) II may be involved i n this process, we investigated its role on the signaling cascade leading t o VCAM-1 expression in endothelial cells. Ang II stimulates mRNA and protei n expression of VCAM-1 in these cells via the AT(1) receptor. This effect w as enhanced by N-G-nitro-L-arginine methyl ester, a nitric oxide synthase i nhibitor, and blocked by pyrrolidinedithiocarbamate, an antioxidant molecul e. Ang II activated the redox-sensitive transcription factor nuclear factor -KB and stimulated the degradation of both inhibitor of kappa B (I kappa B) alpha and I kappa B beta with different kinetics. The degradation of I kapp a Bs induced by Ang II was not modified by incubation with exogenous supero xide dismutase and catalase, suggesting that this effect was not mediated b y the extracellular production of O-2(-). In contrast, rotenone and antimyc in, 2 inhibitors of the mitochondrial respiratory chain, inhibited the Ang II-induced I kappa B degradation, showing that generation of reactive oxyge n species in the mitochondria is involved on Ang II action. BXT-51702, a gl utathione peroxidase mimic, inhibited the effect of Ang II, and aminotriazo le, an inhibitor of catalase, enhanced it, suggesting a role for H2O2 in I kappa B degradation. This is confirmed by experiments showing that Ang II s timulates the intracellular production of H2O2 in endothelial cells. These results demonstrate that Ang II induced an intracellular oxidative stress i n endothelial cells, which stimulates I kappa B degradation and nuclear fac tor-kappa B activation. This activation enhances the expression of VCAM-1 a nd probably other genes involved in the early stages of atherosclerosis.