Effects of kringles derived from human plasminogen on fibrinolysis in vitro.
Plasminogen kringle 1+2+3 (K1-3) containing lysine-binding sites inhibited the reaction of plasmin with alpha 2-plasmin inhibitor (alpha 2PI), in a rate assay using a synthetic chromogenic substrate, S-2251. However, K1-3 did not inhibit the reaction to any degree between alpha 2PI and mini-plasmin which lacked the kringle 1 to 4 portion of plasmin. These results suggest that K1-3 blocked the binding of alpha 2PI to the lysine-binding site of plasmin. In the urokinase (UK)-induced fibrinolysis, K1-3 shortened the human plasma clot lysis time at low concentration (0.5-6 microM), and prolonged the lysis time at a high concentration (20 microM). Similar results were obtained in the lysis time of a fibrin clot consisting of plasminogen, fibrinogen and alpha 2PI isolated from human plasma. The kringle 4 (K4) of human plasminogen did not accelerate human plasma clot lysis at any concentration (1.2-24.1 microM). Furthermore, in the tissue plasminogen activator (TPA)-induced fibrinolysis, K1-3 also shortened both the lysis time of human plasma clot and fibrin clot as observed in UK-induced fibrinolysis, but K4 did not. The above findings indicate that the reaction of alpha 2PI with the lysine-binding site of plasmin is involved in the inhibition of plasmin activity by alpha 2PI, and in the presence of an inhibitor of this reaction, the balance of coagulofibrinolytic activity in plasma will be shifted towards the fibrinolytic side.
Sugiyama
N
N
Research Institute, Daiichi Seiyaku Co., Ltd., Tokyo, Japan.
Iwamoto
M
M
Abiko
Y
Y
D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010958:Plasminogen / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
D010446:Peptide Fragments; D000979:alpha-2-Antiplasmin; C019493:miniplasmin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator