title: Staphylokinase reduces plasmin formation by endogenous plasminogen activators.
abstract: Hyperfibrinolysis is a consequence of imbalance between fibrinolytic activators and their inhibitors. Increased levels of circulating plasminogen (Plg) activators such as tissue- or urokinase-type plasminogen activators (tPA or uPA respectively) are the most common causes of hyperfibrinolysis, occasionally causing major hemorrhages. We found that staphylokinase (SAK), a well-known Plg activator of bacterial origin, inhibits Plg activation mediated by endogenous tPA and uPA. Furthermore, mixture of SAK with tPA led to a significantly reduced Plg-dependent fibrinolysis. This inhibitory effect was exerted through direct action of SAK on Plg rather than indirectly on tPA or uPA. Inhibition of Plg activation by SAK is readily abrogated by interaction of SAK with human neutrophil peptides (HNPs). Finally, we show that NH2-terminal residues of SAK are important for the inhibitory effect of SAK on tPA- and uPA-mediated Plg activation. In conclusion, SAK reduces tPA/uPA-mediated Plg activation by means of SAK.Plg complex formation, consequently downregulating tPA/uPA-induced fibrinolysis.
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Göteborg, Sweden. tao.jin@rheuma.gu.se
authors.forename: Tao
authors.initials: T
authors.lastname: Jin
authors.forename: Maria
authors.initials: M
authors.lastname: Bokarewa
authors.forename: Yihong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Andrej
authors.initials: A
authors.lastname: Tarkowski
mesh_terms: D000328:Adult; D005260:Female; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000494:pharmacology*; D008875:Middle Aged; D010958:Plasminogen / Q000037:antagonists & inhibitors; D010960:Plasminogen Activators / Q000378:metabolism*; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator
chemical_list: D011994:Recombinant Proteins; D010958:Plasminogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases; C022653:auR protein, Staphylococcus aureus