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.
Ohkita
Mamoru
M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094 Japan.
Takaoka
Masanori
M
Sugii
Masato
M
Shiota
Yasuko
Y
Nojiri
Rumi
R
Matsumura
Yasuo
Y
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D013552:Swine
D019332:Endothelin-1; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D009569:Nitric Oxide