Plasminogen activator inhibitor 1 (PAI-1): in vitro activities and clinical relevance

Autor: Anton J. G. Horrevoets
Jazyk: angličtina
Rok vydání: 2004
Předmět:
Zdroj: British journal of haematology. 125(1):12-23
ISSN: 0007-1048
Popis: Plasminogen activator inhibitor 1 (PAI-1) is the main physiological inhibitor of tissue-type and urokinase-type plasminogen activators (t-PA, u-PA). Endothelial or platelet-derived PAI-1 is normally complexed to vitronectin, which prolongs its half-life and makes it the most efficient inhibitor of activated protein C (APC) and thrombin, in the absence of heparin. These target proteinases share a positively charged surface loop (VR-1 or 37-loop), essential for rapid inactivation of the target enzymes. PAI-1 competes with thrombomodulin for binding this surface-loop in thrombin, which, in combination with APC inhibition, makes it a local procoagulant. Vitronectin enhances PAI-1 fibrin-binding, which prevents premature fibrinolysis but also compromises arterial, platelet-rich clot-lysis during pharmacological thrombolysis. Matrix-form vitronectin binds PAI-1 to regulate both u-PA induced pericellular proteolysis and integrin-substratum interactions, thereby influencing cell migration in angiogenesis, cancer and atherosclerosis. PAI-1 has not been established as an independent risk factor for various chronic cardiovascular diseases, caused by the many sites and pathways that integrate into PAI1 plasma levels. A vigorously increased PAI-1 level, however, results in local fibrin deposition in many inflammatory reactions and it strongly predicts the clinical outcome of sepsis by aggravating disseminated intravascular coagulation. Through its interactions with t-PA, thrombin, APC and thrombomodulin, elevated PAI-1 induces a local procoagulant state at the endothelial cell surface, which is aggravated in combination with other procoagulants like factor V-Leiden. The integrity of blood flow is under the continuous surveillance of the coagulation system, ensuring a rapid formation of fibrinstabilized blood clots at sites of injury to the vessel wall, thereby preventing excessive loss of blood from the circulation. Fibrin is formed from fibrinogen through limited proteolysis by thrombin. These thrombin-generated blood clots, however, need to be disposed of as soon as the damaged vessel wall has been repaired. Clot lysis is carried out by the serine protease plasmin, which cleaves multiple peptide bonds in the fibrin matrix, resulting in soluble fibrin degradation products thereby purging the supporting fibrin network of the clot, a process referred to as fibrinolysis. The activity of both coagulation and fibrinolysis needs to be finely tuned to prevent both premature or delayed clot formation and lysis. When bound to the endothelial surface protein thrombomodulin, thrombin also has anticoagulant activities through the protein C pathway, resulting in negative feedback inhibition (Esmon, 2000). Therefore both activation and subsequent inhibition of both thrombin and plasmin are tightly regulated in complex feedback regulatory loops, comprised of multiple zymogens, co-activators and inhibitors (Esmon, 2000). Active plasmin is formed from its inactive zymogen, plasminogen, by the specific proteolytic action of tissue-type plasminogen activator (t-PA). Plasminogen can also be activated by the urokinase-type plasminogen activator (uPA), which, in contrast to t-PA, is only marginally involved in clot-lysis because its presence and activity is mostly confined to tissues. Here, u-PA and plasmin are involved in the proteolysis of matrix proteins during processes like tissue repair and cell migration. The activities of both t-PA and u-PA are controlled by their specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), the main topic of this review. PAI-1 was first purified as a protein secreted by endothelial
Databáze: OpenAIRE
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