Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium.
Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator-inhibitor. High concentrations of thrombin-but not of factor Xa or IXa--had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.
D000818:Animals; D000941:Antigens / Q000096:biosynthesis; D001798:Blood Proteins / Q000096:biosynthesis; D003470:Culture Media; D004727:Endothelium / Q000276:immunology / Q000378:metabolism*; D005169:Factor VIII / Q000096:biosynthesis / Q000276:immunology; D006023:Glycoproteins / Q000096:biosynthesis* / Q000502:physiology*; D006801:Humans; D007519:Isoantigens / Q000096:biosynthesis; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors* / Q000276:immunology; D015849:Plasminogen Inactivators; D011486:Protein C; D013379:Substrate Specificity; D014469:Umbilical Arteries; D014471:Umbilical Veins; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors; D014841:von Willebrand Factor
D000941:Antigens; D001798:Blood Proteins; D003470:Culture Media; D006023:Glycoproteins; D007519:Isoantigens; D015849:Plasminogen Inactivators; D011486:Protein C; C031220:urokinase inhibitor; D014841:von Willebrand Factor; D005169:Factor VIII; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator