Tissue Plasminogen Activator: Chemical and Physiological Aspects

Bachmann, Fédor; Kruithof, Ir Egbert K. O.

doi:10.1055/s-2007-1004403

Cited by 215 publications

(72 citation statements)

References 68 publications

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“…The 10-fold excess of inhibitor relative to PA observed in cultured human umbilical vein endothelial cells by us and others (2-4) is not an exact representation of the in vivo situation; however, there is substantial evidence that in vivo, most if not all of the circulating tPA is bound to PA-I (34). Estimates of blood tPA activity (23,24,(34)(35)(36) range from 0.2 to 2 ng/ml (3-30 pM); whereas tPA antigen (21, 34) is -5-10 ng/ml (75-150 pM). Measurement of PA-I activity has varied widely in different individuals and has ranged from 0 to 120 ng/ml (0-2.4 nM) with an average of 1 nM (23-26, 34, 35).…”

Section: Discussionmentioning

confidence: 86%

Thrombin induction of plasminogen activator-inhibitor in cultured human endothelial cells.

1986

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We have examined the effect of thrombin on the activity of plasminogen activator (PA) and plasminogen activator-inhibitor (PA-I) in medium conditioned by primary cultures of human umbilical vein endothelial cells. PA activity was measured by fibrinolytic and esterolytic assays, and total tissue-type PA (tPA) antigen by radioimmunoassay. Net PA-I activity was assayed by titration of human urokinase esterolytic activity. Incubation of confluent endothelial cell cultures with thrombin for 24 h caused a sixfold increase in PA-I activity. The effect of thrombin was half-maximal at -0.4 U/ml (<4 nM), and required concomitant RNA and protein synthesis. The stimulation of PA-I activity required active a-thrombin and was not obtained with 'y-thrombin nor with thrombin catalytically inactivated with hirudin. Because of the excess of PA-I, PA activity was not measurable in either control or thrombin-treated cells. Thrombin did, however, increase medium concentration of tPA antigen by approximately fourfold. The thrombin-induced PA-I inhibited both tPA and urokinase, did not lose activity upon acidification, and was stable to sodium dodecyl sulfate and thiol reduction. We conclude that physiologic concentrations of thrombin increase both PA-I activity and tPA antigen in medium conditioned by human umbilical vein endothelial cells. Because there was always a several-fold increase in the net activity of free PA-I, these observations suggest that the net effect of thrombin is to decrease fibrinolytic activity in human endothelial cells. Thus, thrombin, in addition to its role in coagulation, may protect clots from premature lysis by increasing the amount of a specific fibrinolytic inhibitor.

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Section: Discussionmentioning

confidence: 86%

Thrombin induction of plasminogen activator-inhibitor in cultured human endothelial cells.

1986

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“…The human fibrinolytic system is comprised of plasminogen, a proenzyme, which can be activated to the active plasmin enzyme by several types of plasminogen activators. The principle endogenous activator of plasminogen is the tissue-type plasminogen activator (tPA) [45] . Plasminogen activator inhibitor (PAI-1), which is produced by platelets, liver, and endothelium, on the other hand, is the major inhibitor of tPA.…”

Section: Dengue Virus-induced Vasculopathymentioning

confidence: 99%

Immunopathogenesis of Dengue Hemorrhagic Fever

Lei¹,

Huang²,

Lin³

et al. 2008

American J. of Infectious Diseases

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Abstract:Dengue virus infection causes Dengue Fever (DF), Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) whose pathogeneses were not clearly understood. A new hypothesis of immunopathogenesis is proposed for the development of the DHF/DSS. An aberrant immune overactivation after dengue virus infection not only impair the immune response to clear the virus, but also result in overproduction of cytokines that affect monocytes, endothelial cells, and hepatocytes, as well as the abnormal production of autoantibodies to platelet and endothelial cells. A molecular mimicry occurs between platelets/endothelial cells and dengue virus antigens. Platelets and endothelial cells are bound by the cross-reactive anti-dengue virus antibodies such as anti-NS1 or anti-prM antibodies. The IFN-γ activated macrophage would phagocytosize the osponized targets. Dengue virus-induced vasculopathy and coagulopathy are involved in the pathogenesis of hemorrhage, and the unbalance between coagulation and fibrinolysis activation increases the likelihood of severe hemorrhage in DHF/DSS. This theory of transient hemophagocytic activity in immunopathogenesis of DHF/DSS can account for specific characteristics of clinical, pathologic, and epidemiological observations in dengue virus infection.

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“…Two types of plasminogen activators exist, namely the urokinase type (uPA) and the tissue-type (tPA). Although there is about 40% structural homology, they have distinct origins and functions (7,23).…”

Section: Proteases Implicated In Invasion and Metastasismentioning

confidence: 99%

“…It is produced by, amongst others, vascular endothelial cells, with a normal plasma level of about 5 ng/ml, of which over 95% is bound to plasminogen activator inhibitor-1 (PAl-1). tPA has a short plasma half-life before being cleared by cells in the liver (23).…”

Section: Tissue Plasminogen Activator (Tpa)mentioning

confidence: 99%