Regulation of low shear flow-induced HAEC VCAM-1 expression and monocyte adhesion

We recently reported that prolonged exposure of human aortic endothelial ce lls (HAEC) to low shear stress flow patterns is associated with a sustained increase in the activated form of the transcriptional regulator nuclear fa ctor-kappa B (NF-kappa B). Here we investigate the hypothesis that low shea r-induced activation of NF-kappa B is responsible for enhanced expression o f vascular cell adhesion molecule (VCAM-1) resulting in augmented endotheli al cell-monocyte (EC-Mn) adhesion and that this activation is dependent on intracellular oxidant activity. Before exposure to low shear (2 dyn/cm(2)) for 6 h, HAEC were preincubated with or without the antioxidants pyrrolidin e dithiocarbamate (PDTC) or N-acetyl-L-cysteine (NAC). PDTC strongly inhibi ted low shear-induced activation of NF-kappa B, expression of VCAM-1, and E C-Mn adhesion. Paradoxically, NAC exerted a positive effect on low shear-in duced VCAM-1 expression and EC-Mn adhesion and only slightly downregulated NF-kappa B activation. However, cytokine-induced NF-kappa B activation and VCAM-1 expression are blocked by both PDTC and NAC. These data suggest that NF-kappa B plays a key role in low shear-induced VCAM-1 expression and tha t pathways mediating low shear- and cytokine-induced EC-Mn adhesion may be differentially regulated.