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A novel mechanism for the inhibition of NFκB activation in vascular endothelial cells by natural antioxidants

The activation of Nuclear Factor κ B (NF‐κB) in vascular endothelial cells, in response to biochemical or biomechanical stimuli, is associated with vascular pathologies such as atherosclerosis. The present manuscript studies the ability of the natural antioxidant– pomegranate wine (PW), to inhibit tumor necrosis factor α (TNF‐α) or shear stress‐mediated– NF‐κB activation in vascular endothelial cells and compares it to that of red wine (RW) and Nacetyl cysteine (NAC). PW and RW act as potent antioxidants in vascular endothelial cells, inhibiting the oxidation of 2',7'‐dichloroflurescin diacetate in TNF‐α treated cells. PW (as well as RW and NAC) acted as potent inhibitors of NF‐κB activation (migration into the nucleus and DNA binding activity) in vascular endothelial cells. Nevertheless, PW and NAC failed to inhibit TNF‐α induced serine 32/36 phosphorylation and IκBα degradation. Surprisingly, these antioxidants alone induced enhanced IκB serine phosphorylation, which was not accompanied by IκBα degradation, or NF‐κB nuclear translocation. This phosphorylation did not involve serine 32/36. Furthermore, we show for the first time that NAC inhibited TNF‐α mediated phosphorylation of p65 (ser536), whereas PW had no effect on this phosphorylation. Thus, natural antioxidants may serve as potent NF‐κB inhibitors in vascular endothelial cells, yet act through unique and divergent pathways.