scholarly journals Changes in the content of some components of the plasminogen activation system in the plasma of bladder cancer patients

2020 ◽  
Vol 80 (1) ◽  
pp. 15-19
Author(s):  
V. Dmytryk ◽  
O. Savchuk ◽  
P. Yakovlev
Keyword(s):  
Bladder Cancer ◽  
Blood Plasma ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Invasion And Metastasis ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator ◽  
Activation System ◽  
Pai 1

Bladder cancer (BC) continues to be a disease with a high mortality rate. Bladder cancer is the sixth for men and seventeenth for women in the incidence of malignancy worldwide. The invasion and metastasis of malignant tumors are caused by a sequence of processes, including loss of cell-cell and / or cell-matrix adhesion, proteolysis, and induction of angiogenesis. Different protease systems are involved in these processes, especially during the invasion and development of metastases. One such protease system is a plasminogen activation system or fibrinolysis system. Changes in the balance of plasminogen activation systems have been investigated in many types of malignancies, and these changes may not only indicate the functioning of this system but may also have prognostic significance. In malignancies, the components of this system are involved in the growth, invasion, and metastasis of tumors, affecting cell migration and angiogenesis. The main, but a well-studied component of the plasminogen activation system is serine proteinase – urokinase-type plasminogen activator (uPA). In contrast to uPA, tissue-type plasminogen activator (tPA) is characterized by a high affinity for fibrin and is involved in thrombolysis. Both types of plasminogen activators are synthesized in tumor tissues: tPA and uPA. The largest player among the inhibitors of fibrinolysis is the plasminogen activator inhibitor type 1 (PAI-1), involved in the pathogenesis of many cardiovascular diseases, as well as in cancer. The purpose of this study was to detect changes in the content of plasminogen activator tissue type tPA and PAI-1 in the blood plasma of patients with BC at different stages of the disease. The study involved 40 men who were verified with a diagnosis of BC. The content of tPA and PAI-1 in preoperative blood plasma was determined by enzyme immunoassay in ELISA modification. In our study, changes in the tPA and PAI-1 content of the blood plasma at different stages were identified, which can characterize tumor growth and invasion and can supplement existing disease information.

Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4212-4215 ◽  
Author(s):  
Daniel T. Eitzman ◽  
Randal J. Westrick ◽  
Zuojun Xu ◽  
Julia Tyson ◽  
David Ginsburg
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Carotid Bifurcation ◽  
Plasminogen Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Atherosclerosis Progression ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.

Plasminogen-dependent and -independent Proteolytic Activity of Murine Endothelioma Cells with Targeted Inactivation of Fibrinolytic Genes

1997 ◽  
Vol 77 (02) ◽  
pp. 362-367 ◽  
Author(s):  
H R Lijnen ◽  
E F Wagner ◽  
D Collen
Keyword(s):  
Extracellular Matrix ◽  
Plasminogen Activator ◽  
Proteolytic Activity ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Matrix Degradation ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Targeted Inactivation ◽  
Pai 1

SummaryPlasminogen-dependent and -independent proteolytic activity of murine endothelioma (End) cells that were derived from mice with targeted inactivation of the tissue-type plasminogen activator (t-PA -/-), urokinase-type plasminogen activator (u-PA-/-) or plasminogen activator inhibitor-1 (PAI-1 -/- genes was studied with the use of fibrin and extracellular matrix degradation assays. In a buffer milieu, the activation rate of plasminogen (final concentration 0.25 µM) with wild-type and t-PA-/- End cells (3 X 104 to 4 X 106 cells/ml) was comparable, but it was about 4-fold reduced with u-PA -/- End cells and 3-fold enhanced with PAI-1End cells. Plasminogen activation was markedly reduced by addition of amiloride or of anti-murine u-PA antibodies but not by addition of anti-murine t-PA antibodies, and it was not stimulated by addition of fibrin. Lysis of125I-fibrin labeled matrix in the presence of plasminogen was comparable with wild-type, t-PA-/- and PAI-1-/- End cells (50% lysis in 3 h with 0.7 to 1.5 X 106 cells/ml), but was significantly reduced with u-PA-/- End cells (50% lysis in 20 h with 0.87 X 106 cells/ml). Lysis of3H-proline labeled extracellular matrix in the presence of plasminogen with wild-type, t-PA-/- and PAI-1-/- End cells (20% lysis in 48 h with 3 to 5 X 106 cells/ml) was comparable, but it was virtually abolished with u-PA-/- End cells. In the absence of plasminogen, lysis of both the fibrin and the extracellular matrix by all four cell types was drastically reduced and was virtually abolished by addition of phenylmethylsulfonylfluoride or 1,10 phenanthroline.These data indicate that the proteolytic activity of the transformed murine endothelioma cells, measured in plasminogen activation or matrix degradation assays, is essentially u-PA-related and largely plasminogen-dependent.

scholarly journals The Plasminogen Activation System Promotes Neurorepair in the Ischemic Brain

2019 ◽  
Vol 20 (9) ◽  
pp. 953-959 ◽  
Author(s):  
Manuel Yepes
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Plasminogen Activator ◽  
Basic Research ◽  
Recovery Phase ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Ischemic Brain ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator

The plasminogen activation (PA) system was originally thought to exclusively promote the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases: tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). However, experimental evidence accumulated over the last 30 years indicates that tPA and uPA are also found in the central nervous system (CNS), where they have a plethora of functions that not always require plasmin generation or fibrin degradation. For example, plasminogen-dependent and - independent effects of tPA and uPA play a central role in the pathophysiological events that underlie one of the leading causes of mortality and disability in the world: cerebral ischemia. Indeed, recent work indicates that while the rapid release of tPA from the presynaptic compartment following the onset of cerebral ischemia protects the synapse from the deleterious effects of the ischemic injury, the secretion of uPA and its binding to its receptor (uPAR) during the recovery phase promotes the repair of synapses that have been lost to the acute ischemic insult. This restorative role of uPA has high translational significance because to this date there is no effective approach to induce neurorepair in the ischemic brain. Here we will discuss recent evidence that bridges the gap between basic research in the field of the PA system and the bedside of ischemic stroke patients, indicating that uPA and uPAR are potential targets for the development of therapeutic strategies to promote neurological recovery among ischemic stroke survivors.

scholarly journals Hormonal control of plasmin and tissue-type plasminogen activator activity in rat milk during involution of the mammary gland

2000 ◽  
Vol 167 (2) ◽  
pp. 265-273 ◽  
Author(s):  
E Tonner ◽  
GJ Allan ◽  
DJ Flint
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Insulin Like Growth Factor ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Igf I ◽  
Pai 1

We have proposed that growth hormone (GH) and prolactin (PRL) interact to suppress apoptosis in the mammary gland. GH increases insulin-like growth factor-I (IGF-I) synthesis whereas PRL suppresses the production of insulin-like growth factor-binding protein-5 (IGFBP-5) in the epithelial cells, which would otherwise inhibit IGF-mediated cell survival. IGFBP-5 was present in milk from involuting glands at high concentrations (approximately 60 microg/ml) and had a high affinity (8.03 x 10(-10) M) for IGF-I, suggesting an inhibitory effect of IGFBP-5 in the mammary gland. IGFBP-5 was present in the micellar fraction of milk and binds specifically to alpha(s2)-casein. Since alpha(s2)-casein also binds plasminogen and tissue-type plasminogen activator (t-PA), resulting in the conversion of plasminogen to plasmin, and since IGFBP-5 binds to plasminogen activator inhibitor-1 (PAI-1), we investigated whether apoptosis and extracellular matrix (ECM) degradation might be coordinately controlled by GH and PRL possibly acting through IGFBP-5. Litters were removed from lactating rats to initiate involution. Plasminogen activation and t-PA activity were both increased dramatically after 48 h and GH and PRL suppressed this response. By contrast, 17beta-oestradiol, progesterone or corticosterone did not influence either process. An antiserum to IGF-I, which blocked systemic IGF-I effects, failed to inhibit the activation of plasminogen or the increase in t-PA, suggesting that paracrine effects of IGF-I may be more important. Teat-sealing, which led to the accumulation of milk without hormonal changes, also led to increases in plasminogen activation and t-PA activity, suggesting that locally produced factors (of which IGFBP-5 is one) are important in controlling ECM remodelling. We propose that GH and PRL inhibit apoptosis and ECM remodelling by a process that involves the control of IGF-I and PAI-1 availability by IGFBP-5, thus allowing these processes to be tightly coordinated.

Tamoxifen-Induced Changes in the Plasma Fibrinolytic Factors in Menopausal Women with Breast Cancer

1997 ◽  
Vol 3 (4) ◽  
pp. 234-238 ◽  
Author(s):  
Charles D. Lox ◽  
Catherine A. Ronaghan ◽  
Everardo Cobos ◽  
Robert H. Messer
Keyword(s):  
Breast Cancer ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Enzyme Linked Immunosorbent Assay ◽  
Invasion And Metastasis ◽  
Type Plasminogen Activator ◽  
Menopausal Women ◽  
Before And After ◽  
Pai 1 ◽  
Over Time

There is evidence that tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), and the plasminogen activator inhibitors 1 and 2 (PAI-1, PAI-2), are involved in the invasion and metastasis of breast tumors. Menopausal controls and menopausal women with breast cancer, who were taking tamoxifen, 10 mg b.i.d., had plasma antigenic levels of tPA, uPA, PAI-1, and PAI-2 determined by enzyme-linked immunosorbent assay (ELISA). In addition, five women being placed on this tamoxifen regimen also had these same determinations made before and after 6 months. Significant increases were observed for tPA, uPA, and PAI-1 in the 26 tamoxifen-treated patients. The percent increase in tPA and uPA combined were greater than that of PAI-1. Nonsignificant increases were also seen in the five women evaluated before and after initiation of treatment. Linear correlations were seen for tPA and PAI-1 over time length of exposure to tamoxifen. Ratios of tPA/PAI- 1 and UPA/PAI-1 were not significantly different, but were correlated and linear. From these data, it appears that tamoxifen increases the fibrinolytic factors in these patients and that this was not proportional as the ratios of the factors were not different after treatment. The increase in activators was greater than inhibitors, which could be detrimental in terms of the potential for invasion and metastasis of the tumor cell. As a negative correlation was seen for tPA over time while PAI- was positively correlated, this may help explain why some patients taking tamoxifen are at risk for thromboembolytic events. Key Words: TPA—uPA—PAI-1—PAI-2—Tamoxifen—Breast cancer.

scholarly journals The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

2021 ◽  
Vol 10 (3) ◽  
pp. 518
Author(s):  
Filomena Napolitano ◽  
Nunzia Montuori
Keyword(s):  
Plasminogen Activator ◽  
Blood Clot ◽  
Active Form ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Scientific Debate ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Normal Blood Flow

The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. The plasminogen activation (PA) system includes urokinase-type plasminogen activator (uPA), tissue-type PA (tPA), and two types of plasminogen activator inhibitors (PAI-1 and PAI-2). In addition to the regulation of fibrinolysis, the PA system plays an important role in other biological processes, which include degradation of extracellular matrix such as embryogenesis, cell migration, tissue remodeling, wound healing, angiogenesis, inflammation, and immune response. Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. Different forms of angioedema are linked to uncontrolled activation of coagulation and fibrinolysis systems. Moreover, plasmin itself can induce a potentiation of bradykinin production with consequent swelling episodes. The number of studies investigating the PA system involvement in angioedema has grown in recent years, highlighting its relevance in etiopathogenesis. In this review, we present the components and diverse functions of the PA system in physiology and its importance in angioedema pathogenesis.

Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4212-4215 ◽  
Author(s):  
Daniel T. Eitzman ◽  
Randal J. Westrick ◽  
Zuojun Xu ◽  
Julia Tyson ◽  
David Ginsburg
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Carotid Bifurcation ◽  
Plasminogen Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Atherosclerosis Progression ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Activator Inhibitor ◽  
Pai 1

Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.

Differential Role of Components of the Fibrinolytic System in the Formation and Removal of Thrombus Induced by Endothelial Injury

1999 ◽  
Vol 81 (04) ◽  
pp. 601-604 ◽  
Author(s):  
Hiroyuki Matsuno ◽  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Shigeru Ueshima ◽  
Osamu Matsuo ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Thrombus Formation ◽  
Endothelial Injury ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Clot Lysis ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Pai 1

SummaryThe role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

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