부산대학교 도서관

Extracellular histones inhibit tissue plasminogen activator (t-PA)-mediated fibrinolysis by modifying fibrin structure and rheological properties. However, other plasminogen activators involved in intravascular and extravascular fibrinolysis have not been considered yet. We investigated the effect of histones on fibrinolysis driven by different plasminogen activators. Clot lysis induced by t-PA, urokinase (u-PA) and its single chain precursor (scu-PA) was evaluated by turbidimetry. Conversion of scu-PA to u-PA and activation of factor seven activating protease (FSAP) were assessed by fluorogenic and chromogenic assays, respectively. Histones delayed t-PA- and u-PA-mediated fibrinolysis but strongly accelerated scu-PA-driven clot lysis through the enhancement of scu-PA to u-PA conversion. This effect required a plasma factor identified as FSAP by the following findings: 1) histones enhanced neither scu-PA activation nor scu-PA-mediated clot lysis under purified conditions; 2) in plasma, the enhancement of fibrinolytic activity by histones was abolished by a neutralizing anti-FSAP antibody; and 3) histones promoted the activation of plasma FSAP. The effect of the natural mixture of histones on scu-PA-driven fibrinolysis was differentially recapitulated by the individual recombinant histones, H4 displaying the strongest activity. When complexed to DNA, histones still accelerated scu-PA-mediated fibrinolysis but with a lesser efficiency due to a reduced FSAP activation. Finally, preincubation of histones with heparin or activated protein C, two known inhibitors of histones, further amplified histone-mediated boost of scu-PA-driven fibrinolysis. Enhancement of FSAP-mediated scu-PA activity by histones may play yet unforeseen roles in intravascular fibrinolysis and contribute to extravascular proteolysis and tissue damage. • Histones have been reported to inhibit t-PA-induced fibrinolysis. • At variance, we show that histones stimulate scu-PA-driven fibrinolysis. • Histones promote FSAP activation, which then converts scu-PA to fully active u-PA. • Histones may play variable roles in intra- and extra-vascular fibrin(proteo)lysis. [ABSTRACT FROM AUTHOR]