Plasminogen activator inhibitor-1

Mottonen, J., et al. Structural basis of latency in plasminogen activator inhibitor-1. Nature 355 270-273, 1992. 

A number of adipokines are linked to inflammation and immunity (Fig. 1). This includes both leptin and adiponectin, and also a number of other key inflammatory proteins, particularly cytokines and chemokines [1]. The cytokines and chemokines encompass interleukin-1(3 (EL-1 (3), IL-6, DL-10, TNFa, monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF). Other major inflammation-related adipokines include nerve growth factor (NGF), and acute phase proteins such as serum amyloid A and haptoglobin. In addition, adipocytes secrete plasminogen activator inhibitor-1 (PAI-1), which is an important thrombotic factor as well as an acute phase protein. 

Figure 51-7. Scheme of sites of action of streptokinase, tissue plasminogen activator (t-PA), urokinase, plasminogen activator inhibitor, and Kj-antiplasmin (the last two proteins exert inhibitory actions). Streptokinase forms a complex with plasminogen, which exhibits proteolytic activity this cleaves some plasminogen to plasmin, initiating fibrinolysis. 

Inhibits platelet aggregation by increasing levels of cAMP Binds protein C, which is then cleaved by thrombin to yield activated protein C this in combination with protein S degrades factors Va and Villa, limiting their actions Activates plasminogen to plas-min, which digests fibrin the action of t-PA is opposed by plasminogen activator inhibitor- (PAI-1)... 

Plasminogen activator Plasminogen activator inhibitor-1 Tissue inhibitor of metalloproteinase... 

Plasminogen activator inhibitors have been shown to be present in a large variety of different cells and tissues. These inhibitors are thought to play an important role in regulating tissue fibrinolysis. One of these inhibitors has been purified from cultured bovine aortic epithelial cells. This inhibitor has been shown to be a serine protease inhibitor and inhibits the function of two proteolytic enzymes urokinase and tissue plasminogen activator, both of which cleave and activate plasminogen. The mechanism by which this inhibitor functions is very similar to that described above with a-l-PI. Thus, the inhibitor forms a binary complex with the proteolytic enzyme and thereby inhibits its activity. Again in a situation comparable to that with a-l-PI, it was found that when the purified bovine aortic epithelial inhibitor was exposed to Al-chlorosuccinimide,... 

PAI Plasminogen activator inhibitor PA-IgG Platelet associated immunoglobulin G PAM Pulmonary alveolar macrophages... 

DVT, deep vein thrombosis HIT, heparin-induced thrombocytopenia PAI-I, plasminogen activator inhibitor PE, pulmonary embolism SERM, selective estrogen receptor modulator VTE, venous thromboembolism. 

BMI body mass index PAI-1 plasminogen activator inhibitor-1... 

Fio. 3. The intrinsic and extrinsic cascade fibrinolytic systems. activation H, inhibition t-PA, tissue plasminogen activator PAI, plasminogen activator inhibitor a2-M, a2-macroglobulin a2-AP, a2-antiplasmin. 

The procoagulant factors produced by endothelial cells are the coagulation factors von Willebrand factor (WF), F-V, F-VIII, tissue factor (TF), and plasminogen activator inhibitor (PAI), which blocks the activators u-PA and t-PA and counteracts fibrinolysis (G21, FI6). It has been shown that under the influence of complement activation (C9), in response to endotoxin in vitro (C24), in experimental E. coli sepsis in baboons (D30), and after stimulation with TNF (Al, N6), endothelial cells up-regulate the expression of TF, down-regulate TM and inhibit the production of t-PA and PAF. Thus, the balance may shift in the procoagulant direction with a large excess of PAI-1. 

F16. De Fouw, N. J., Van Hinsbergh, V. W. M., De Jong, Y. F Haverkate, F., and Bertina, R. M., The interaction of activated protein C and thrombin with the plasminogen activator inhibitor released from human endothelial cells. Thromb. Haemost. 57, 176-182 (1987). 

Plasminogen activator inhibitor type 2 (PAI-2) is present in human placenta and monocytes (37, 42). The single-chain inhibitor molecule (sPAI-2) inhibits both two-chain u-PA and two-chain t-PA. Its inhibition is 10 times greater for two-chain u-PA compared with two-chain t-PA and it inhibits single-chain t-PA only minimally (37). Plasma concentrations of PAI-2 up to 2 p,M have been observed in the third trimester of pregnancy (42). 

Other plasminogen activator inhibitors are PAI-3, which is believed to be identical to the activated protein C inhibitor, and proteinase nexin 1, found in the renal epithelial cells, cytosol of fibroblasts, and cardiac myocytes (37, 42, 44, 45). 

The measurement of plasminogen activator inhibitor-1 (PAI-1), which complexes with tissue plasminogen activator (t-PA) and thus affects the ability of the latter to activate fibrinolysis, is useful in the assessment of fibrinolytic disorders (93). The complex formed by the fibrinolytic enzyme plasmin with its inhibitor... 

Some physiological variables influence the measurement of fibrinolytic activators and inhibitors. For instance, both t-PA and plasminogen activator inhibitor 1 (PAI-1) levels in plasma are subject to diurnal variation in a 12-hour period. Even in samples taken at the same time of day the coefficient of variation (CV) of measured PAI levels range from 8 to 143% To account for this diurnal variation, blood samples spaced over several time intervals during a 24-hour period should be collected. Consumption of alcohol induces the PAI level in plasma. The half-life of t-PA is 360 seconds. However, in the presence of trauma or inflammation, when the PAI-1 level is expected to be elevated 10-fold, the half-life of t-PA is reduced to 36 seconds (114). 

Sprengers E. D Kluft C. Plasminogen activator inhibitors. Blood 1987 69, 381-7. 

Levin E. G., Santell L. Association of a plasminogen activator inhibitor (PAI-1) with the growth substratum and membrane of human endothelial cells. J Cell Biol 1987 105, 2543-9. 

Heeb M. J., Espana F Geiger M. Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor 3. J Biol Chem 1987 262,15813-6. 

Wygrecka, M., Morty, R.E., Markart, P., Kanse, S.M., Andreasen, P.A., Wind, T., Guenther, A., and Klaus, T.P. (2007) Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of factor VILactivating protease in patients with acute respiratory distress syndrome. J. Biol. Chem., 10.1074/jbc.M610748200, published online ahead of print. 

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