Glutathione peroxidase potentiates the inhibition of platelet function by S-nitrosothiols.
GSH peroxidase (Px) catalyzes the reduction of lipid hydroperoxides (LOOH), known metabolic products of platelets and vascular cells. Because interactions between these cells are modulated by nitric oxide (NO) and LOOH inactivate NO, we investigated the effect of GSH-Px on the inhibition of platelet function by the naturally occurring S-nitrosothiol, S-nitroso-glutathione (SNO-Glu). Concentrations of SNO-Glu that alone did not inhibit platelet function (subthreshold inhibitory concentrations) were added to platelet-rich plasma together with GSH-Px (0.2-20 U/ml); this led to a dose-dependent inhibition of platelet aggregation with an IC50 of 0.6 U/ml GSH-Px. In the presence of subthreshold inhibitory concentrations of SNO-Glu, the LOOH, 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid, increased platelet aggregation, an effect reversed by GSH-Px. Glutathione and SNO-Glu were equally effective as cosubstrates for GSH-Px. Incubation of SNO-Glu with GSH-Px for 1 min led to a 48.5% decrease in the concentration of SNO-Glu. Incubation of SNO-Glu with serum albumin led to the formation of S-nitroso-albumin, an effect enhanced by GSH-Px. These observations suggest that GSH-Px has two functions: reduction of LOOH, thereby preventing inactivation of NO, and metabolism of SNO-Glu, thereby liberating NO and/or supporting further transnitrosation reactions.
Freedman
J E
JE
Whitaker Cardiovascular Institute, Boston University School of Medicine, Massachusetts 02118, USA.
Frei
B
B
Welch
G N
GN
Loscalzo
J
J
D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000097:blood; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D004357:Drug Synergism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000494:pharmacology*; D006801:Humans; D008054:Lipid Peroxides / Q000494:pharmacology; D008623:Mercaptoethanol; D009603:Nitroso Compounds / Q000378:metabolism / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D026422:S-Nitrosoglutathione; D026403:S-Nitrosothiols; D013482:Superoxide Dismutase / Q000494:pharmacology
D008054:Lipid Peroxides; D009603:Nitroso Compounds; D010975:Platelet Aggregation Inhibitors; D026403:S-Nitrosothiols; D026422:S-Nitrosoglutathione; D008623:Mercaptoethanol; C032635:S-nitrosomercaptoethanol; C021315:S-nitrosocysteine; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D006152:Cyclic GMP; D003545:Cysteine