Differential modulation of prostaglandin H synthase-2 by nitric oxide-related species in intact cells

Nitrogen monoxide (NO) has been reported to both activate and inhibit prost aglandin (PG) biosynthesis. This apparent paradox might be explained by the production/action of distinct NO-related species formed as a result of the prevailing redox states of different cellular systems. As such, the effect of NO donors with different redox characteristics on the modulation of pro staglandin H synthase-2 (PGHS-2) in primary mouse cortical astrocytes and C OS-7 cells engineered to overexpress PGHS-2 was assessed. In general, compo unds that released NO. or NO- enhanced, while a peroxynitrite (OONO-) gener ator inhibited, PGHS-2-dependent prostaglandin production. While the possib ility of altered gene transcription was eliminated in the COS-7 system as P GHS-2 was maximally expressed, in primary astrocytes where PGHS-2 expressio n was induced by lipopolysaccharide (LPS), effects on protein expression we re detected. Compounds that released NO. synergistically enhanced LPS-media ted PGHS-2 protein synthesis. None of these effects were mediated by cGMP. All donors lost their ability to modulate PGHS-2 expression and function wh en decayed. These results indicate that the ultimate effect of NO on PGHS-2 enzyme activity and expression is dictated by the prevalent NO-related spe cies formed, suggesting that important interactions which may exist between NO and prostanoid pathways in vivo will be highly dependent on the inheren t redox environment.