Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study underscores a regulatory role of intracellular ceramide in astrocytes for the release of an extracellular serine protease, tissue-type plasminogen activator (t-PA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1). Treatment of cultured human astrocytes with N-acetylsphingosine, a cell-permeable short-chain ceramide analogue or daunorubicin that could increase intracellular ceramide via activation of ceramide synthase or sphingomyelin hydrolysis increased the release of t-PA and conversely decreased the PAI-1 release. Interestingly, treatment of the astrocytes with tumor necrosis factor (TNF)-alpha also increased the intracellular ceramide levels but caused the elevation of PAI-1 release without altering the t-PA release. These data suggest that the generation of ceramide in astrocytes is linked at least with the regulation of PAI-1 release. We also demonstrate that the suppression of PAI-1 release with daunorubicin accelerates the cell death of neuronally differentiated PC12 cells and suggest an antiapoptotic role of PAI-1 in the nervous system.
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PMID:Release of plasminogen activator inhibitor-1 from human astrocytes is regulated by intracellular ceramide. 1110 62

Wound healing is a complex process involving the interactions of many different cell types, matrix components and biological factors, including proteinases and cytokines. This study compared the levels of proteinases (matrix metalloproteinases and plasminogen activators), proteinase inhibitors (tissue inhibitors of metalloproteinases and plasminogen activator inhibitors), inflammatory cytokines and growth factors in acute wound fluid samples collected from the surgical drains of elective breast (n = 24) and colorectal (n = 26) patients on the first postoperative day. Gelatin zymography was used to determine matrix metalloproteinase-2 and -9 levels, quenched fluorescence substrate hydrolysis was applied for total MMP activity and enzyme-linked immunoassays were used to quantitate other factors. Colorectal wound fluid samples showed significantly (p < 0.05) greater levels of the matrix metalloproteinases (MMP-1, 2, 3, and 9), tissue inhibitor of metalloproteinases-1, urokinase plasminogen activator receptor and the inflammatory cytokines (interleukin-1beta, -6, and tumor necrosis factor-alpha); e.g., matrix metalloproteinase-3 colon; median 275 (range 11-2.530) ng/ml; breast; 530-400. However, tissue plasminogen activator and growth factor levels (epidermal growth factor, platelet-derived growth factor, basic fibroblast growth factor, transforming growth factor-beta1) were significantly greater in breast samples; e.g., epidermal growth factor breast 468 (103-1, 444) pg/ml; colon 57(1-573). There was no difference in the levels of urokinase type plasminogen activator, plasminogen activator inhibitor-1 and -2, tissue inhibitor of metalloproteinases -2 or vascular endothelial growth factor. Acute wound fluid from different surgical wounds showed different profiles of proteinases, proteinase inhibitors, and cytokines. This may lead to differences in the rate of tissue remodeling and therefore healing in these two wounds in vivo.
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PMID:Proteinases, their inhibitors, and cytokine profiles in acute wound fluid. 1111 51

Pentoxifylline (PTX) has been demonstrated to improve graft survival in renal transplant recipients undergoing post graft complications. As activated monocytes are possible initiators of vascular damage through tissue factor (TF) expression, we evaluated the monocyte TF expression and endothelium activation markers in 140 consecutive patients receiving cadaveric kidney grafts, randomized in a double-blind study comparing PTX versus placebo. Monocyte TF expression and plasma von Willebrand factor, tissue plasminogen activator, thrombomodulin and tumor necrosis factor-alpha (TNF-alpha) levels were determined before transplantation and each month after. Additional samplings were realized in case of acute rejection. TF and TNF-alpha expression were significantly modified after graft. In patients with complications, PTX prevented the increase of TF expression at month one, and after rejection episodes. Endothelium activation markers were significantly modified after graft and in patients with complications but PTX had no significant effect on their plasma levels. These results suggest that the protective effect of PTX on graft survival could be related to the prevention of monocyte TF upregulation associated with complications.
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PMID:Pentoxifylline prevents upregulation of monocyte tissue factor in renal transplant recipients undergoing post-graft complications. 1112 52

This study investigated the relationship between the circulating levels of the endothelial cell glycoproteins plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (TPA), and thrombomodulin (TM) and the major vascular risk factors described in dialysis patients. In addition, the role of these endothelial cell products as independent predictors of coronary artery disease (CAD) was analyzed. Levels of TM, TPA antigen (Ag), TPA activity, PAI-1 Ag, PAI-1 activity, TPA/PAI complexes, thrombin-antithrombin complexes, fibrinopeptide A, C-reactive protein (CRP), interleukin-1beta and tumor necrosis factor-alpha, lipids, apoproteins A1 and B, and albumin were measured in a group of 200 nondiabetic dialysis patients and 100 healthy matched volunteers. When compared with healthy controls, dialysis patients showed increased levels of CRP, TM, TPA, and PAI-1 and evidence of increased thrombin-dependent fibrin formation. Increased levels of active PAI-1 were associated to a great extent with major classic vascular risk factors and to a lesser extent with CRP and serum triglycerides. Forty-six patients (23%) had evidence of CAD. Variables associated with CAD in the univariate analysis included age, time on dialysis, male gender, number of packs of cigarettes per year, high BP, fibrinogen, apolipoprotein B, albumin, PAI-1 activity, CRP, thrombin-antithrombin complexes, and fibrinopeptide A. Logistic regression analysis found age, high-density lipoprotein cholesterol, gender, high BP, CRP, time on dialysis, and PAI-1 activity to be independent predictors of CAD. This model classified correctly 85% of patients as having CAD and showed adequate goodness of fit for all risk categories. Our data support a pathogenic link among activated inflammatory response, endothelial injury, and CAD in hemodialysis patients and suggest that assessment of circulating PAI-1 levels could be an additional tool to identify dialysis patients who are at risk for developing atheromatous cardiovascular disease.
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PMID:Circulating levels of plasminogen activator inhibitor type-1, tissue plasminogen activator, and thrombomodulin in hemodialysis patients: biochemical correlations and role as independent predictors of coronary artery stenosis. 1137 50

Obesity is related to cardiovascular disease (CVD) morbidity and mortality, however, the mechanisms for the development of obesity-induced CVD risk remain unclear. Hyperinsulinemia and insulin resistance are considered key components in the metabolic cardiovascular syndrome and as independent risk factors for CVD. Plasma leptin and tumor necrosis factor-alpha (TNF-alpha), two adipocyte products, are also proposed to be associated with the development of CVD risk. The purpose of this study is to evaluate the association of plasma leptin, soluble TNF receptors (sTNF-R), and insulin levels as possible mediators of the effect of obesity on atherogenic and thrombogenic CVD risk factors among men. From the Health Professionals Follow-up Study (HPFS), we selected 268 men, aged 47--83 years, who were free of CVD, diabetes, and cancer (except non-melanoma skin cancer), and who had provided a fasting blood sample in 1994. We measured plasma insulin and leptin levels by radioimmunoassay and sTNF-R levels by ELISA. Men in the highest quintile of body mass index (BMI, mean=30.5 kg/m(2)) were less physically active and had a more adverse cardiovascular lipid and homeostatic profile, as indicated by levels of insulin, triglyceride (TG), tissue plasminogen activator (t-PA) antigen levels, and apolipoprotein A1 (Apo-A1). In a multivariate regression model controlling for age, smoking, alcohol intake, physical activity and diet, BMI was inversely associated with HDL-cholesterol (HDL-C) and Apo-A1 and positively associated with TG, Apo-B and t-PA antigen levels. The associations between BMI and these CVD risk factors were only slightly changed after adjusting for leptin and/or sTNF-R; but were substantially attenuated after controlling for insulin levels. These data suggest that the association between obesity and biological predictors of CVD may be mediated through changes in plasma insulin, rather than leptin or sTNF-R levels. However, plasma leptin may still play a role in CVD through independent effects on lipid metabolism.
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PMID:Plasma insulin, leptin, and soluble TNF receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men. 1147 52

The effects of tumor necrosis factor (TNF)-alpha on the plasminogen activator (PA)/plasmin system in human dental pulp (HDP) cells were examined. TNF-alpha treatment induced a significantly high level of PA activity in the conditioned medium of HDP cells in a time- and dose-dependent manner, compared with untreated control cells. Western-blot analysis revealed that tissue type (t)PA protein in conditioned medium was increased by TNF-alpha when compared with control medium. Furthermore the tPA mRNA level had increased in HDP cells treated with TNF-alpha, as determined by reverse transcription-polymerase chain reaction, but urokinase PA and PA inhibitor-1 mRNA levels did not increase. We examined the effects of TNF-alpha against activities of matrix metalloproteinases (MMPs) using zymography. TNF-alpha stimulated MMP-2 activity in conditioned medium and stimulated MMP-9 activity with addition of plasminogen into conditioned medium. The present results suggested that TNF-alpha stimulates PA activity via an enhancement of tPA gene expression in HDP cells and MMP-2 activity, and further that tPA-activated TNF-alpha stimulated MMP-9.
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PMID:Stimulation of plasminogen activator activity and matrix metalloproteinases of human dental pulp-derived cells by tumor necrosis factor-alpha. 1148 46

In a prospective clinical study of 50 patients with Dengue Shock Syndrome (DSS), we investigated the association of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), and IL-6 with activation markers of coagulation (F1+2 and TATc) and fibrinolysis (t-PA, PAPc, and D-dimer). We found that TNF-alpha, IL-1beta and Il-1Ra, but not IL-6, concentrations were elevated in the circulation during the early stage of infection and at discharge from hospital. TNF-alpha was significantly associated with D-dimer, an activation marker of fibrinolysis (p < 0.003), but not with activation markers of coagulation. IL-1beta was significantly associated with t-PA (p < 0.03). IL-1Ra was significantly associated with F1+2, TATc (p < 0.04 and p < 0.02, respectively), whereas IL-6 was significantly associated with both, activation markers of coagulation (F1+2; p < 0.03) and fibrinolysis (PAPc; p = 0.002). Our data are in line with studies in bacterial sepsis. In severe dengue virus infection the same cytokines are involved in the onset and regulation of hemostasis.
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PMID:The role of cytokines in activation of coagulation and fibrinolysis in dengue shock syndrome. 1185 87

Although hypertension, hyperlipidemia, diabetes and smoking are known risk factors of atherosclerosis in Caucasians, their relative contributions to early atherosclerosis among Japanese are unknown. Decrease in flow-mediated dilation (FMD) of the brachial artery is a useful marker of endothelial dysfunction and early atherosclerosis. To evaluate the relative contribution of hypertension to early atherogenesis, we determined FMD, as well as plasma levels of tissue-type plasminogen activator (t-PA; a sensitive index of endothelial damage) and tumor necrosis factor (TNF)-a and interleukin (IL)-6 (established markers of inflammation) in normotensive and hypertensive patients under treatment. FMD was significantly reduced as the number of risk factors increased, suggesting that accumulations of risk factors were related to endothelial dysfunction. FMD was reduced in hypertensives (9.9 +/- 5.8 (SD) %) compared to normotensives (14.6 +/- 7.6, p<0.01) despite good blood pressure control (139 +/- 20/80 +/- 14 mmHg in hypertensives). Nitroglycerine-induced endothelium-independent vasodilation was not altered in hypertensives (16.0 +/- 6.3%) as compared to normotensives (16.7 +/- 5.8). Plasma t-PA, TNF-alpha, and IL-6 levels were increased in hypertensives despite good blood pressure control. Thus, hypertension alone is a high risk for early atherosclerosis. Persistent endothelial damage and moderate inflammation may increase the risk of early atherosclerosis synergistically under the presence of hypertension in Japanese.
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PMID:Association of cardiovascular risk factors and endothelial dysfunction in japanese hypertensive patients: implications for early atherosclerosis. 1213 29

Systemic inflammation because of sepsis results in endothelial cell activation and microvascular injury. High-mobility group protein-1 (HMGB1), a novel inflammatory molecule, is a late mediator of endotoxin shock and is present in the blood of septic patients. The receptor for advanced glycation end products (RAGE) is expressed on endothelium and is a receptor for HMGB1. Here we examine the effects of HMGB1 on human endothelial cell function. Recombinant human HMGB1 (rhHMGB1) was cloned and expressed in Escherichia coli and incubated with human microvascular endothelium. rhHMGB1 caused a dose- and time-dependent increase in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and RAGE. rhHMGB1 induced the secretion of tumor necrosis factor-alpha (TNFalpha), interleukin 8 (IL-8), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) (P <.01). rhHMGB1 stimulation resulted in transient phosphorylation of mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), and p38, and in nuclear translocation of transcription factors NF-kappaB and Sp1. These effects are partially mediated by TNFalpha autocrine stimulation, as anti-TNFalpha antibodies significantly decrease chemokine and adhesion molecule responses (P </=.002). Thus, rhHMGB1 elicits proinflammatory responses on endothelial cells and may contribute to alterations in endothelial cell function in human inflammation.
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PMID:Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. 1245 6

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, while laminar flow and high shear stress are atheroprotective. Well characterized atheroprotective mechanisms include inhibition of thrombosis (increased tissue-type plasminogen activator and decreased plasminogen activator inhibitor-1), inhibition of endothelial cell apoptosis, limitation of permeability (uptake of low-density lipoprotein), prevention of white blood cell binding and transmigration (no expression of adhesion molecules such as intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1] and no release of monocyte chemotactic protein-1) and increased bioavailability of nitric oxide (because of increased expression of endothelial nitric oxide synthase and manganese superoxide dismutase). Our lab has investigated flow-mediated inhibition of inflammatory cytokine action. In particular, we have shown that flow prevents tumor necrosis factor-alpha (TNF-alpha) mediated signal transduction. TNF regulates inflammatory gene expression (e.g., ICAM-1 and VCAM-1) in endothelial cells, in part, by stimulating mitogen activated protein (MAP) kinases that phosphorylate transcription factors. We hypothesized that fluid shear stress inhibits TNF inflammatory effects on endothelial cells by inhibiting TNF mediated activation of the c-Jun N-terminal kinase. To test this hypothesis, we determined the effects of steady laminar flow on TNF-stimulated activity of c-Jun N-terminal kinase. The results show that flow inhibits c-Jun N-terminal kinase activation through multiple mechanisms, including stimulation of counter-regulatory MAP kinases (extracellular signal regulated kinases [ERK]1/2 and ERK5) and inhibition of apoptosis signal-regulated kinase. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms. These multiple mechanisms offer attractive targets for new drug therapies aimed at limiting atherosclerosis development and progression. (c) 2002 Prous Science. All rights reserved.
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PMID:Atheroprotective Mechanisms Activated by Fluid Shear Stress in Endothelial Cells. 1267 55


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