S-nitrosylation of tissue-type plasminogen activator confers vasodilatory and antiplatelet properties on the enzyme.
Tissue-type plasminogen activator (t-PA) reacts upon exposure to endothelium-derived relaxing factor (EDRF) by way of the enzyme's single free sulfhydryl (Cys-83) to form a stable S-nitrosothiol protein adduct. S-nitrosylation endows t-PA with potent vasodilatory and antiplatelet properties that are accompanied by elevations in intracellular cyclic GMP analogous to those induced by low molecular weight (e.g., S-nitroso amino acid) S-nitrosothiols. Moreover, this chemical modification does not adversely affect the catalytic efficiency of t-PA, the fibrin stimulation of this activity, the binding of t-PA to fibrinogen, or the interaction of the enzyme with its physiologic serine protease inhibitor, plasminogen-activator inhibitor type I. The coupling of vasodilatory, antiplatelet, and fibrinolytic properties in one molecule makes the S-nitrosylated t-PA a unique molecular species and may provide insight into the mechanisms by which the endothelium maintains vessel patency. These data also suggest a pharmacologic approach to treatment of thromboocclusive disorders.
Stamler
J S
JS
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Simon
D I
DI
Jaraki
O
O
Osborne
J A
JA
Francis
S
S
Mullins
M
M
Singel
D
D
Loscalzo
J
J
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009603:Nitroso Compounds / Q000737:chemistry* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010959:Tissue Plasminogen Activator / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014665:Vasodilator Agents
D009603:Nitroso Compounds; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D005337:Fibrin; D005340:Fibrinogen; D010959:Tissue Plasminogen Activator; D006152:Cyclic GMP