Inhibitory effects of nitric oxide on the expression and activity of aromatase in human granulosa cells.
The aim of the present study was to explore the mechanisms by which nitric oxide (NO) may inhibit aromatase activity of human granulosa cells. Ovarian granulosa-luteal cells, obtained from patients undergoing in-vitro fertilization (IVF) were cultured in the presence of NO-related substances. After 24 h of culture, aromatase activity of the cells was significantly inhibited by treatment with the NO donors, SNAP or NOC12 at > or =10(-4) M in a dose-dependent manner. Treatment with NO catabolites or a peroxynitrite-releasing compound, SIN1, had no significant influence. Treatment with SNAP at 10(-3) M decreased relative aromatase mRNA values by 72% (P<0.05) and intracellular cyclic AMP concentrations by 53% (P<0.01). However, treatment with H89, an inhibitor of protein kinase A, did not inhibit aromatase activity. Since there were no significant effects of NO catabolites or peroxinitrite, the inhibitory action of NO donors on aromatase must be related to NO release. The action of NO is, in part, attributable to the down-regulation of aromatase gene transcription. Although NO decreased intracellular cAMP values, down-regulation of aromatase gene transcription may not be mediated by protein kinase A-dependent mechanisms.
Kagabu
S
S
Department of Obstetrics and Gynecology, Akita University School of Medicine, Japan.
Kodama
H
H
Fukuda
J
J
Karube
A
A
Murata
M
M
Tanaka
T
T
D000328:Adult; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism*; D047072:Aromatase Inhibitors; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006107:Granulosa Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009566:Nitrates / Q000378:metabolism / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012977:Sodium Nitrite / Q000494:pharmacology; D013449:Sulfonamides; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009566:Nitrates; C110881:S-nitro-N-acetylpenicillamine; D013449:Sulfonamides; C039642:peroxynitric acid; D009569:Nitric Oxide; C031618:sodium nitrate; D000242:Cyclic AMP; D001141:Aromatase; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010396:Penicillamine; D012977:Sodium Nitrite; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013755:Tetradecanoylphorbol Acetate