The role of nuclear factor-kappa B 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-kappaB (NF-kappaB) plays an important role in endothelin-1 production. In the present study, we investigated the possible involvement of NF-kappaB 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-kappaB 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-alpha-induced endothelin-1 production and NF-kappaB activation in endothelial cells. In addition, we found that FK409 suppressed NF-kappaB activation by the induction and stabilization of the inhibitory protein alpha, IkappaBalpha. Taken together, our results suggest that NO modulates the endothelial endothelin-1 production, possibly through the regulation of NF-kappaB activation.