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Free Content C1-inhibitor prevents non-specific plasminogen activation by a prourokinase mutant without impeding fibrin-specific fibrinolysis

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Background: Prourokinase (prouPA) is unstable in plasma at therapeutic concentrations. A mutant form, M5, made more stable by reducing its intrinsic activity was therefore developed. Activation to two-chain M5 (tcM5) induced a higher catalytic activity than two-chain urokinase plasminogen activator (tcuPA), implicating an active site functional difference. Consistent with this, an unusual tcM5 complex with plasma C1-inhibitor was recently described in dog and human plasma. The effect of C1-inhibitor on fibrinolysis and fibrinogenolysis by M5 is the subject of this study. Methods and results: Zymograms of tcM5 and tcuPA incubated in plasma revealed prominent tcM5–C1-inhibitor complexes, which formed within 5 min. The inhibition rate by purified human C1-inhibitor (250 μg mL−1) was about 7-fold faster for tcM5 than it was for tcuPA (10 μg mL−1). The effect of the inhibitor on the stability of M5 and prouPA was determined by incubating them in plasma at high concentrations (10–20 μg mL−1) ± C1-inhibitor supplementation. Above 10 μg mL−1, depletion of all plasma plasminogen occurred, indicating plasmin generation and tcM5/tcuPA formation. With supplemental C1-inhibitor, M5 stability was restored but not prouPA stability. Clot lysis by M5 ± supplemental C1-inhibitor showed no attenuation of the rate of fibrinolysis, whereas fibrinogenolysis was prevented by C1-inhibitor. Moreover, because of higher dose-tolerance, the rate of fibrin-specific lysis reached that achievable by non-specific fibrinolysis without inhibitor. Conclusions: Plasma C1-inhibitor stabilized M5 in its proenzyme configuration in plasma by inhibiting tcM5 and thereby non-specific plasminogen activation. At the same time, fibrin-specific plasminogen activation remained unimpaired. This unusual dissociation of effects has significant implications for improving the safety and efficacy of fibrinolysis.
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Keywords: C1-inhibitor; fibrin-specificity; fibrinolysis; mutant prourokinase

Document Type: Research Article

Publication date: 01 May 2007

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