Oxidized fibrin stimulates the activation of pro-urokinase and is the preferential substrate of human plasmin.
Activated phagocytes participate in physiological thrombolysis producing non-radical excited oxidants and the important proteases elastase and urokinase. The interaction of oxidized fibrin with the proteases of the fibrinolytic system is therefore physiologically relevant. Here it is shown that human pro-urokinase is activated three- to four-fold faster in the presence of an oxidized solid fibrin matrix. In contrast, oxidized fibrin did not favour the fibrinolytic activity of urokinase or t-PA. Measurement of urokinase antigen showed that urokinase bound slightly to strongly oxidized denatured fibrin, whereas pro-urokinase did not. Plasmin degraded oxidized fibrin more rapidly than non-oxidized fibrin. Thus, singlet molecular oxygen (1O2) converts fibrin to a form that stimulates the activation of plasminogen (bound to oxidized fibrin) by pro-urokinase and that of pro-urokinase by plasmin. The oxidative modification of fibrin by 1O2 is specific. In contrast to oxygen radicals (H2O2 in high concentration) 1O2 does not directly destroy protein chains but favours subsequent fibrinolysis. Thus 1O2 prepares fibrin for its specific degradation.
Stief
T W
TW
Thrombosis and Hemostasis Section, University Hospital Seville, Spain.
D004789:Enzyme Activation / Q000187:drug effects; D005337:Fibrin / Q000737:chemistry / Q000494:pharmacology*; D005341:Fibrinolysin / Q000378:metabolism*; D005342:Fibrinolysis; D006801:Humans; D016877:Oxidants; D010084:Oxidation-Reduction; D010586:Phagocytes; D010958:Plasminogen; D011994:Recombinant Proteins; D013379:Substrate Specificity; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D016877:Oxidants; D011994:Recombinant Proteins; D005337:Fibrin; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase