The cyclooxygenase hydroperoxide product PGG(2) activates synaptic nitric oxide synthase: a possible antioxidant response to membrane lipid peroxidation.
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 G(2) (PGG(2)) greatly stimulated NOS activity in synaptosomal membrane fractions from rat brain in a dose-dependent (EC(50) = 0.2 microM) 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 PGH(2) and 15-HETE or by hydrogen peroxide. These findings demonstrate that PGG(2)-activated synaptic NOS by a hydroperoxide-mediated pathway and support the view that NOS activation may be an important physiological response to lipid peroxidation.
Foley
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TD
Biochemistry Program, University of Scranton, Scranton, Pennsylvania 18510, USA. foleyt2@uofs.edu
D000818:Animals; D004789:Enzyme Activation; D015227:Lipid Peroxidation; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D018384:Oxidative Stress; D011462:Prostaglandins G / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology*
D011462:Prostaglandins G; C038291:prostaglandin G2; D019001:Nitric Oxide Synthase