The role of nuclear factor-κB in the regulation of endothelin-1 production by nitric oxide

Nitric oxide (NO) has been reported to have an inhibitory effect on endothelin-1 production, but the detailed mechanisms are poorly understood. Our previous studies showed that a transcription factor nuclear factor-κB (NF-κB) plays an important role in endothelin-1 production. In the present study, we investigated the possible involvement of NF-κB in the inhibitory regulation of endothelin-1 production by NO. 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (carboxy-PTIO), which is a well-known NO scavenger, remarkably increased both endothelin-1 production and NF-κB activation in cultured vascular endothelial cells. On the other hand, a spontaneous NO donor (±)-( E)-4-ethyl-2-[( E)-hydroxyimino]-5-nitro-3-hexanamide (FK409) significantly attenuated the basal and tumor necrosis factor-α-induced endothelin-1 production and NF-κB activation in endothelial cells. In addition, we found that FK409 suppressed NF-κB activation by the induction and stabilization of the inhibitory protein alpha, IκBα. Taken together, our results suggest that NO modulates the endothelial endothelin-1 production, possibly through the regulation of NF-κB activation.