The molecular interaction between plasminogen activators and type 1 plasminogen activator inhibitor

Abstract

The fibrinolytic system in mammalian blood comprises an inactive proenzyme, plasminogen, which is activated to the proteolytic enzyme plasmin by two immunologically distinct physiologic plasminogen activators (PA), tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Inhibition may occur either at the level of the PA, by specific PA inhibitors (PAI), or at the level of plasmin, mainly by ~_-antiplasmin. t-PA is primarily responsible for removal of fibrin from the vascular tree; it ~as a specific affinity for fibrin and produces clot-restricted plasminogen activation. Impairment of fibrinolysis, associated with thrombosis, may be due to a defective synthesis and/or release of t-PA from the vessel wall, to a deficiency or functional abnormality in the molecular interactions regulating plasminogen activation or to increased levels of inhibitors of t-PA or of plasmin. On the other hand, excessive fibrinolysis due to increased levels of t-PA or to deficiency of ~2-antiplasmin or PAI, may result in a bleeding tendency, u-PA lacks affinity for fibrin and requires conversion from a single chain to a two chain molecule to be fully active, u-PA binds to a specific cell-surface receptor and is believed to be primarily involved in cell-mediated proteolytic events such as wound healing, macrophage invasion, ovulation, angiogenesis and tumor invasion. In m~n, PAI-I deficiency results in delayed rebleeding; genetic deficiencies of t-PA or u-PA have not yet been reported. Recently, the effect of PAI-I gene inactivation on hemostasis, thrombosis and thrombolysis was studied in homozygous PAI-l-deficient mice, generated by homologous recombination in embryonic stem cells. Disruption of the PAI-I gene appeared to induce a mild hyperfibrinolytic state and a greater resistance to venous thrombosis, but not to impair hemostasis. This may suggest some phenotypic dissimilarity between mouse ~nd man. Furthermore, the role of t-PAand u-PA-mediated plasminogen activation in development, reproduction, thrombolysis, thrombosis and macrophage function has been studied in mice with single and combined inactivation of the t-PA and/or u-PA genes. Mice with single deficiencies of t-PA and u-PA developed normally, were fertile and bad a normal life span. t-PA-deficient mice bad a reduced thrombolytic potential, whereas u-PA-deficient mice occasionally developed spontaneous fibrin deposits in tissues and displayed deficient plasmin-mediated macrophage function. Mice with combined deficiency of t-PA and u-PA survived embryonic development, but showed extensive fibrin deposition and suffered retarded postnatal growth, reduced fertility and shortened life span. These findings indicate that t-PA and u-PA have divergent roles in fibrinolysis and macrophage function and that they may cooperate in complex biological processes.