Gene Review

SERPINE1  -  serpin peptidase inhibitor, clade E (nexin...

Homo sapiensSynonyms: Endothelial plasminogen activator inhibitor, PAI, PAI-1, PAI1, PLANH1, ...Koh, K.K. et al., Czekay, R.P. et al., Foekens, J.A. et al., Cubellis, M.V. et al., Levin, E.G. et al., et al.

We hypothesized that therapy with a mutant human PAI-1 (PAI 1R) that binds to matrix vitronectin but does not inhibit plasminogen activators, would enhance plasmin generation, increase matrix turnover, anddecrease matrix accumulation in experimental glomerulonephritis [2]. These recent findings emphasize the involvement of PAI-1 in controlling the biology of adipose tissue; PAI-1 is an attractive new therapeutictarget to retard the metabolic complications that accompany obesity [8]. An LGI diet reduces fasting plasma PAI-1 activity and therefore may beuseful for diminishing the adverse cardiovascular effects of obesity [10]. It is possible to reduce plasma PAI-1 by changes in life style, e.g. weight reduction and physical activity [14]. BACKGROUND: Plasma levels of plasminogen-activator inhibitor type 1(PAI-1), an essential inhibitor of fibrinolysis in humans, increase in women after menopause, and this may contribute to the risk of cardiovascular disease [16]. CONCLUSIONS: Conjugated estrogen, alone or combined with progestin therapy, reduced PAI-1 levels by approximately 50 percent in postmenopausal women and was associated with enhanced systemic fibrinolysis [16]. Serine  proteinase inhibitors, including plasminogen activator inhibitortype 1 (PAI-1) and antithrombin, are key regulators of hemostatic processes such as thrombosis and wound healing [20]. Its effects on ROS production, AP-1 activity, plasminogen activatorinhibitor 1 (PAI-1) gene expression, and cellular proliferation and migration were measured in response to high glucose and angiotensin II (Ang-II) concentrations, two major factors in the pathogenesis of atherosclerosis in patients with diabetes and hypertension [21]. We provide evidence that this balance between cell adhesion and cell detachment is governed by PA inhibitor-1 (PAI-1) [22]. Beneficial effects of gemfibrozil in reducing coronary events in hypertriglyceridemic patients may depend, in part, on potentiation of fibrinolysis by direct diminution of synthesis of endogenous PAI-1 [17]. The rapid deposition and predominance of PAI-1 in the underlying compartment of endothelial cells may explain how the basement membrane is protected from proteolytic degradation by plasmin-generating enzymes [25]. This pathway may represent a general mechanism, since PAI-1 also can detach cells from fibronectin and type-1 collagen [23]. The identification of platelet VN and its binding to platelet PAI-1 raises the possibility that VN, in contrast to other adhesive proteins, may participate in localized regulatory functions of blood coagulation and fibrinolysis in platelet-matrix interactions and the protection of the matrix against proteolysis [31].

Our results demonstrate that PAI-1 may regulate uPA initiated cell signaling by a mechanism that requires VLDLr recruitment [39]. Binding of PAI-1 to endothelial cells stimulated by thymosin beta 4 and modulation of their fibrinolytic potential [42]. The cleavage and inactivation of PAI-1 by HNE was shown to be a novel pathway to enhance fibrinolysis [34]. PAI-1 mRNA and protein expression were seen in human coronary artery atherectomy specimens as well and were localized to analogous monocyte/macrophages and to smooth muscle cells as judged from results of in situ hybridization and immunocytochemistry studies [48]. BACKGROUND: In patients with established ischemic heart disease, prospective cohort studies have indicated that plasminogen activatorinhibitor (PAI-1), the inhibitor of the fibrinolytic system, may predict cardiovascular events [49].

References

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33. Smad6s regulates plasminogen activator inhibitor-1 through a protein kinase C-beta- dependent up-regulation of transforming growth factor-beta. Berg, D.T., Myers, L.J., Richardson, M.A., Sandusky, G., Grinnell, B.W. J. Biol. Chem. (2005) [Pubmed]34. The cleavage and inactivation of plasminogen activator inhibitor type 1 by neutrophil elastase: the evaluation of its physiologic relevance in fibrinolysis. Wu, K., Urano, T., Ihara, H., Takada, Y., Fujie, M., Shikimori, M., Hashimoto, K., Takada, A. Blood (1995) [Pubmed]35. Inactivation of plasminogen activator inhibitor-1 by specific proteolysis with stromelysin-1 (MMP-3). Lijnen, H.R., Arza, B., Van Hoef, B., Collen, D., Declerck, P.J. J. Biol. Chem. (2000) [Pubmed]36. 19F NMR studies of plasminogen activator inhibitor-1.  Abbott, G.L., Blouse, G.E., Perron, M.J., Shore, J.D., Luck, L.A., Szabo, A.G. Biochemistry (2004)[Pubmed]37. Conformational changes of the reactive-centre loop and beta-strand 5A accompany temperature-dependent inhibitor-substrate transition of plasminogen-activator inhibitor 1. Kjøller, L., Martensen, P.M., Sottrup-Jensen, L., Justesen, J., Rodenburg, K.W., Andreasen, P.A. Eur. J. Biochem. (1996) [Pubmed]38. Differential mechanisms targeting type 1 plasminogen activator inhibitor and vitronectin into the storage granules of a human megakaryocytic cell line. Hill, S.A., Shaughnessy, S.G., Joshua, P., Ribau, J., Austin, R.C., Podor, T.J. Blood (1996) [Pubmed]39. Plasminogen activator inhibitor 1 functions as a urokinase response modifier at the level of cell signaling and thereby promotes MCF-7 cell growth. Webb, D.J., Thomas, K.S., Gonias, S.L. J. Cell Biol. (2001) [Pubmed]40. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. Dennler, S., Itoh, S., Vivien, D., ten Dijke, P., Huet, S., Gauthier, J.M. EMBO J. (1998) [Pubmed]41. Both Max and TFE3 cooperate with Smad proteins to bind the plasminogen activator inhibitor-1 promoter, but they have opposite effects on transcriptional activity. Grinberg, A.V., Kerppola, T. J. Biol. Chem. (2003)[Pubmed]42. Binding of PAI-1 to endothelial cells stimulated by thymosin beta4 and modulation of their fibrinolytic potential. Boncela, J., Smolarczyk, K., Wyroba, E., Cierniewski, C.S. J. Biol. Chem. (2006) [Pubmed]43. The variable region-1 from tissue-type plasminogen activator confers specificity for plasminogen activator inhibitor-1 to thrombin by facilitating catalysis: release of a kinetic block by a heterologous protein surface loop. Dekker, R.J., Eichinger, A., Stoop, A.A., Bode, W., Pannekoek, H., Horrevoets, A.J. J. Mol. Biol. (1999) [Pubmed]44. Plasminogen activator inhibitor-1 is an inhibitor of factor VII-activating protease in patients with acute respiratory distress syndrome. Wygrecka, M., Morty, R.E., Markart, P., Kanse, S.M., Andreasen, P.A., Wind, T., Guenther, A., Preissner, K.T. J. Biol. Chem. (2007) [Pubmed]45. Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products. van Hinsbergh, V.W., Bauer, K.A., Kooistra, T., Kluft, C., Dooijewaard, G., Sherman, M.L., Nieuwenhuizen, W. Blood (1990) [Pubmed]46. Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1 (PAI-1) promoter regulates TNF alpha -induced PAI-1 expression. Gruber, F., Hufnagl, P., Hofer-Warbinek, R., Schmid, J.A., Breuss, J.M., Huber-Beckmann, R., Lucerna, M., Papac, N., Harant, H., Lindley, I., de Martin, R., Binder, B.R. Blood (2003) [Pubmed]47. alpha-2 Macroglobulin receptor/Ldl receptor-related protein(Lrp)-dependent internalization of the urokinase receptor. Conese, M., Nykjaer, A., Petersen, C.M., Cremona, O., Pardi, R., Andreasen, P.A., Gliemann, J., Christensen, E.I., Blasi, F. J. Cell Biol. (1995) [Pubmed]48. Modulation of expression of monocyte/macrophage plasminogen activator activity and its implications for attenuation of vasculopathy. Lundgren, C.H., Sawa, H., Sobel, B.E., Fujii, S. Circulation (1994) [Pubmed]49. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Thögersen, A.M., Jansson, J.H., Boman, K., Nilsson, T.K., Weinehall, L., Huhtasaari, F., Hallmans, G. Circulation (1998) [Pubmed]