Nitric oxide inhibits endothelin-1 production through the suppression of nuclear factor kappa B.
We have reported previously that the nitric oxide (NO) donor FK409 [(+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexanamide] improved renal dysfunction as well as renal lesions in rats with ischaemia/reperfusion injury. We also found that FK409 substantially reduced endothelin-1 (ET-1) production in cultured vascular endothelial cells (ECs). Nuclear factor kappa B (NF-kappa B) is known to play a key role in the development of ischaemic disorders through regulation of the expression of a variety of genes. In the present study, we examined the effects of FK409 on ET-1 production in cultured pig aortic ECs, and the possible involvement of NF-kappa B in the inhibitory effect of NO on ET-1 production. FK409 significantly attenuated basal and tumour necrosis factor-alpha (TNF-alpha)-induced preproET-1 mRNA expression in ECs. In addition, FK409 diminished basal and TNF-alpha-stimulated NF-kappa B activation in ECs. Pretreatment with N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal or BAY 11-7082, both of which are suppressors of NF-kappa B activation, effectively attenuated basal and TNF-alpha-induced ET-1 mRNA expression. These findings suggest that the suppression of NF-kappa B activation is at least partly involved in the FK409-induced inhibition of ET-1 production in ECs. We propose that NF-kappa B activation plays an important role in ET-1 production.
Ohkita
Mamoru
M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Takaoka
Masanori
M
Shiota
Yasuko
Y
Nojiri
Rumi
R
Matsumura
Yasuo
Y
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D019332:Endothelin-1 / Q000096:biosynthesis*; D016232:Endothelins / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D013552:Swine
D019332:Endothelin-1; D016232:Endothelins; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D011498:Protein Precursors; D012333:RNA, Messenger; C061872:FK 409