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The inhibition of TNK-t-PA by C1-inhibitor

2001; Lippincott Williams & Wilkins; Volume: 12; Issue: 1 Linguagem: Inglês

10.1097/00001721-200101000-00011

1473-5733

Thomas Sulikowski, P A Patston,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

TNK-t-PA is a recombinant mutant of tissue plasminogen activator that has a longer half-life and higher selectivity for fibrin than normal tissue plasminogen activator (t-PA). In addition, it is reported to be serpin resistant because of reduced inhibition by plasminogen activator inhibitor-1. In this study, we have investigated the inhibition of TNK-t-PA by the serpin C1-inhibitor. TNK-t-PA is inhibited with a second-order rate constant of 7.5 per mol/l per s compared with 4.5 per mol/l per s for t-PA. In both cases, the stoichiometry was close to 20, indicating that C1-inhibitor was predominantly a substrate for both forms of t-PA. The formation of cleaved C1-inhibitor was seen on sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE), and the t-PA–C1-inhibitor (or TNK-t-PA–C1-inhibitor) complex seen on SDS–PAGE and by zymography. Although the rates of inhibition are very slowin vitro, the fact thatin vivoformation of the t-PA–C1-inhibitor complex after infusion of t-PA has been well documented suggests that TNK-t-PA will also be inhibited by C1-inhibitorin vivoand, perhaps more importantly, could cause a significant reduction in C1-inhibitor concentration.