NITRIC OXIDE-DEPENDENT INDUCTION OF GLUTATHIONE SYNTHESIS THROUGH INCREASED EXPRESSION OF GAMMA-GLUTAMYLCYSTEINE SYNTHETASE

The nitric oxide (NO) donors S-nitrosopenicillamine or DetaNONOate, wh ich release NO at a rate of 0-15 nM sec(-1), were exposed to rat aorti c vascular smooth muscle cells for a period of 0-24 h. This treatment resulted in an increase in total glutathione levels of two- to threefo ld under conditions where no cytotoxicity was detected. The signaling pathways do not involve activation of protein kinase G I alpha nor are they cGMP dependent. Oxidation of reduced glutathione (GSH) was found after exposure to NO for 3-4 h at rates of formation at or above 8 nM sec-l. Increased intracellular GSH was due to enhanced expression of the rate-limiting enzyme for GSH synthesis, gamma-glutamylcysteine syn thetase, Since NO has been shown previously to protect cells against o xidative stress, we propose that the increase in GSH: by NO is a poten tial mechanism for enhancing the antioxidant defenses of the cell. Thi s result also has important implications for identifying redox-sensiti ve cell signaling pathways that can be activated by NO. (C) 1998 Acade mic Press.