The Cyclooxygenase Hydroperoxide Product PGG2 Activates Synaptic Nitric Oxide Synthase: A Possible Antioxidant Response to Membrane Lipid Peroxidation

Abstract

Nitric oxide is a potent inhibitor of membrane lipid peroxidation. It is unknown, however, whether nitric oxide synthase (NOS) activity increases under conditions of membrane lipid peroxidation. Importantly, cyclooxygenase (COX)-catalyzed peroxidation of arachidonic acid is well-established to be increased by lipid hydroperoxides. The results of the present study demonstrate that the COX hydroperoxide product prostaglandin G2 (PGG2) greatly stimulated NOS activity in synaptosomal membrane fractions from rat brain in a dose-dependent (EC50 = 0.2 μM) manner in the presence of ATP and the antioxidant urate. NOS activation was also produced, albeit to a lesser extent, by 15-hydroperoxyeicosatetraenoic acid (15-HPETE) but not by the corresponding hydroxy compounds PGH2 and 15-HETE or by hydrogen peroxide. These findings demonstrate that PGG2-activated synaptic NOS by a hydroperoxide-mediated pathway and support the view that NOS activation may be an important physiological response to lipid peroxidation.