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Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis | Bentham Science

Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. (E-pub Abstract Ahead of Print)Author(s): Tetsumei Urano, Department of Medical Physiology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Japan Yuko Suzuki, Department of Medical Physiology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Japan Takayuki Iwaki, Department of Pharmacology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Japan Hideto Sano, Department of Medical Physiology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Japan Naoki Honkura, Department of Medical Physiology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Japan Francis J Castellino. W.M. Keck Center for Transgene Research, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United StatesAffiliation:Journal Name: Current Drug Targets DOI : 10.2174/1389450120666190715102510  Journal HomeAbstract: . The fibrinolytic system is composed of a balance between rates of plasminogen activation and fibrin degradation, both of which are finely regulated by spatio-temporal mechanisms. Three distinct inhibitors of the fibrinolytic system that differently regulate these steps are: plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin, and thrombin activatable fibrinolysis inhibitor (TAFI). In this review, we focus on the mechanisms by which PAI-1 governs total fibrinolytic activity to provide its essential role in many hemostatic disorders, including fibrinolytic shutdown after trauma. PAI-1 is a member of the serine protease inhibitor superfamily (SERPIN) and inhibits the protease activities of plasminogen activators (PAs) by forming complexes with PAs, thereby regulating fibrinolysis. The major PA in the vasculature is tissue-type PA (tPA) which is secreted from vascular endothelial cells (VECs) as an active single chain form. Since PAI-1 exists in molar excess to tPA in plasma, and forms an inactive complex with high affinity, the amount of free active tPA, as well as its activity in plasma, is simply determined by the balance of the molar concentrations of these two proteins. Further, PAI-1 in plasma facilitates the release of active tPA which is retained on the surface of VECs by forming a tPA-PAI-1 complex that suppresses fibrinolytic potential on VECs. Thus, elevated plasma levels of PAI-1 are directly related to attenuated fibrinolysis and increased risk for thrombosis. Since plasma PAI-1 levels are highly elevated under a variety of pathological conditions, including infection/inflammation, fibrinolytic potential, both in plasma and VECs, are readily suppressed to induce fibrinolytic shutdown. A congenital deficiency of PAI-1 in humans, in turn, leads to life-threatening bleeding. These considerations attest to the fact that PAI-1 is the primary regulator of the initial step of fibrinolysis and governs total fibrinolytic activity. Keywords: plasminogen activator inhibitor type 1 (PAI-1), fibrinolysis, trauma, fibrinolysis shutdown Rights & PermissionsPrintExport Cite as× Current Drug Targets. Title:Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis VOLUME: 20 Author(s):Tetsumei Urano, Yuko Suzuki, Takayuki Iwaki, Hideto Sano, Naoki Honkura and Francis J Castellino Affiliation:Department of Medical Physiology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Department of Medical Physiology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Department of Pharmacology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Department of Medical Physiology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Department of Medical Physiology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, 431-3192, W.M. Keck Center for Transgene Research, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana Keywords:plasminogen activator inhibitor type 1 (PAI-1), fibrinolysis, trauma, fibrinolysis shutdown Abstract:The fibrinolytic system is composed of a balance between rates of plasminogen activation and fibrin degradation, both of which are finely regulated by spatio-temporal mechanisms. Three distinct inhibitors of the fibrinolytic system that differently regulate these steps are: plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin, and thrombin activatable fibrinolysis inhibitor (TAFI). In this review, we focus on the mechanisms by which PAI-1 governs total fibrinolytic activity to provide its essential role in many hemostatic disorders, including fibrinolytic shutdown after trauma. PAI-1 is a member of the serine protease inhibitor superfamily (SERPIN) and inhibits the protease activities of plasminogen activators (PAs) by forming complexes with PAs, thereby regulating fibrinolysis. The major PA in the vasculature is tissue-type PA (tPA) which is secreted from vascular endothelial cells (VECs) as an active single chain form. Since PAI-1 exists in molar excess to tPA in plasma, and forms an inactive complex with high affinity, the amount of free active tPA, as well as its activity in plasma, is simply determined by the balance of the molar concentrations of these two proteins. Further, PAI-1 in plasma facilitates the release of active tPA which is retained on the surface of VECs by forming a tPA-PAI-1 complex that suppresses fibrinolytic potential on VECs. Thus, elevated plasma levels of PAI-1 are directly related to attenuated fibrinolysis and increased risk for thrombosis. Since plasma PAI-1 levels are highly elevated under a variety of pathological conditions, including infection/inflammation, fibrinolytic potential, both in plasma and VECs, are readily suppressed to induce fibrinolytic shutdown. A congenital deficiency of PAI-1 in humans, in turn, leads to life-threatening bleeding. These considerations attest to the fact that PAI-1 is the primary regulator of the initial step of fibrinolysis and governs total fibrinolytic activity.Close Print this page ×Export File: RIS (for EndNote, Reference Manager, ProCite) BibTeX TextContent: Citation Only Citation and Abstract Close× About this article. Cite this article as: Tetsumei Urano, Yuko Suzuki, Takayuki Iwaki, Hideto Sano, Naoki Honkura and Francis J Castellino, “Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis”, Current Drug Targets (2019) 20: 1. https://doi.org/10.2174/1389450120666190715102510 DOI https://doi.org/10.2174/1389450120666190715102510. Print ISSN 1389-4501. Publisher Name Bentham Science Publisher. Online ISSN 1873-5592. About this journalClose Article Details (E-pub Abstract Ahead of Print) DOI: 10.2174/1389450120666190715102510 Price: $95 Journal Insight .