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

In addition to lowering blood lipids, clinical benefits of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A; EC 1.1.1.34) reductase inhibitors may derive from altered vascular function favoring fibrinolysis over thrombosis. We examined effects of pitavastatin (NK-104), a relatively novel and long acting statin, on expression of tissue factor (TF) in human monocytes (U-937), plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator (t-PA) in human aortic smooth muscle cells (SMC) and human umbilical vein endothelial cells (HUVEC). In monocytes, pitavastatin reduced expression of TF protein induced by lipopolysaccharide (LPS) and oxidized low-density lipoprotein (OxLDL). Similarly, pitavastatin also reduced expression of TF mRNA induced by LPS. Pitavastatin reduced PAI-1 antigen released from HUVEC under basal, OxLDL-, or tumor necrosis factor-alpha (TNF-alpha)-stimulated conditions. Reductions of PAI-1 mRNA expression correlated with decreased PAI-1 antigen secretion and PAI-1 activity as assessed by fibrin-agarose zymography. In addition, pitavastatin decreased PAI-1 antigen released from OxLDL-treated and untreated SMC. Conversely, pitavastatin enhanced t-PA mRNA expression and t-PA antigen secretion in untreated OxLDL-, and TNF-alpha-treated HUVEC and untreated SMC. Finally, pitavastatin increased t-PA activity as assessed by fibrin-agarose zymography. Our findings demonstrate that pitavastatin may alter arterial homeostasis favoring fibrinolysis over thrombosis, thereby reducing risk for thrombi at sites of unstable plaques.
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PMID:Pitavastatin alters the expression of thrombotic and fibrinolytic proteins in human vascular cells. 1293 53

Fibrin is a temporary matrix which not only covers a wound, but also provides a structure for invading cells during healing. Changes in the polymerization conditions before gelation of the clot affect the structure of fibrin and thus might influence the interaction with invading cells. Therefore we tested whether changes in the fibrin structure influence the formation of capillary-like tubular structures by human microvascular endothelial cells (hMVEC) in an in vitro angiogenesis model. Opaque [125I]fibrin structures prepared at pH 7.0, fibrin matrices at pH 7.4 and transparent [125I]fibrin structures prepared at pH 7.8 were neutralized (pH 7.4) before seeding hMVEC on top of them in confluent density. Endothelial cells were stimulated with a growth factor [basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)165] and a cytokine [tumor necrosis factor (TNF)-alpha] to induce the u-PA/u-PA receptor-dependent formation of capillary-like tubular structures. The formation of these structures was quantified by determining the length of the invasive structures by image analysis and by measuring the accompanying [125I]fibrin degradation. Ingrowth of tubular structures proceeded at a faster rate in opaque matrices consisting of thick fibrin fibers as compared to transparent gels with fine fibrin fibers. The more rapid ingrowth of tubular structures in opaque fibrin gels induced by bFGF/TNF-alpha or VEGF165/TNF-alpha was accompanied by a larger extent of fibrin degradation. Both processes were inhibited by aprotinin and epsilon-aminocaproic acid indicating the involvement of plasmin. They were also inhibited by anti-u-PA or anti-u-PA receptor IgG, but not by anti-t-PA IgG, suggesting the involvement of cell-bound u-PA activity. However, in the opaque fibrin gels, the tubular structures dissolved upon prolonged incubation due to excessive fibrin degradation. Simulation of hMVEC with bFGF alone did not induce tubular structures, but ca used a high degree of t-PA- and plasmin-dependent fibrin lysis, and, after several days, a partial detachment of sheets of cells. Gradual inhibition of the excessive fibrin degradation by a series of aprotinin concentrations did not lead to tube formation in bFGF-treated cells. These data indicate that the formation and stability of tubular structures by hMVEC in fibrin is accompanied by controlled fibrinolysis and depends critically not only on cell-bound u-PA-dependent plasminogen activation, but also on the fibrin structure. Because the fibrin structure is largely influenced by the conditions in which fibrin has been polymerized, these conditions may have considerable impact on angiogenesis during wound healing and vascularization of tumour stroma.
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PMID:Influence of fibrin structure on the formation and maintenance of capillary-like tubules by human microvascular endothelial cells. 1451 71

Periodontal disease is a chronic infection of the gums characterized by a loss of attachment between the tooth and bone, and by bone loss. We evaluated cross-sectionally the association between periodontal disease and C-reactive protein (CRP), fibrinogen, factor VII, tissue plasminogen activator (t-PA), LDL-C, von Willebrand factor, and soluble tumor necrosis factor receptors 1 and 2. The final sample consisted of 468 men (ages 47-80 yrs), participating in the Health Professional Follow-up Study, who provided blood and were free of CVD, diabetes, and cancer. In multivariate regression models controlling for age, cigarette smoking, alcohol intake, physical activity, and aspirin intake, self-reported periodontal disease was associated with significantly higher levels of CRP (30% higher among periodontal cases compared with non-cases), t-PA (11% higher), and LDL-C (11% higher). Based on our data, periodontal disease showed significant associations with biomarkers of endothelial dysfunction and dyslipidemia, which may potentially mediate the association between periodontal and cardiovascular disease.
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PMID:Periodontal disease and biomarkers related to cardiovascular disease. 1474 54

The effects of cerivastatin and fenofibrate on proteins involved in haemostasis and on markers of inflammation were investigated in otherwise healthy middle-aged males with combined hyperlipidemia. Besides classical risk factors, other so-called novel risk factors for coronary artery disease are seen to be playing an increasingly important role in the development and progression of atherosclerosis. Thirty-eight males, aged 49 +/-5 years were randomised to 12 weeks treatment either with cerivastatin at a daily dose of 0.2 mg to 0.4 mg to achieve the LDL cholesterol goal of <3.0 mM, or with fenofibrate 250 mg daily. Fasting serum lipids, homocysteine, total and free tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (t-PA) antigen and activity, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured. No change in homocysteine level was observed in the cerivastatin group, while after fenofibrate administration it increased (p <0.0001). Total TFPI decreased significantly after cerivastatin (p = 0.002), but not after fenofibrate. Free TFPI did not decrease after either drug. Neither drug affected (t-PA) antigen and activity, while fenofibrate increased PAI-1 antigen (p <0.05) and activity (p <0.05). Cerivastatin decreased serum CRP values by 49.5% (p = 0.001), and fenofibrate by 29.8% (p = 0.03). The decreases of CRP in the two groups differed significantly (p = 0.04). IL-6 levels decreased significantly in the fenofibrate group (39%; p <0.0001), but not in the cerivastatin group (15%; p = 0.24) No significant decreases were observed for TNF-alpha. Cerivastatin had neutral effects on fibrinolysis, homocysteine or coagulation. On the other hand, fenofibrate increased PAI-1 antigen and activity and homocysteine, and did not affect coagulation. Both cerivastatin and fenofibrate reduced CRP levels, the decrease being significantly greater after cerivastatin. Fenofibrate also significantly decreased IL-6.
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PMID:Statin and fibrate treatment of combined hyperlipidemia: the effects on some novel risk factors. 1554 43

Stroke is the third leading cause of death and the leading cause of permanent disability in western countries and the incidence of stroke is expected to increase in the foreseeable future due to the ageing population. The effective treatment of stroke remains challenging due to the complexity and heterogenicity of the disease. Recombinant tissue plasminogen activator (rt-PA) is the only FDA-approved therapy for stroke during the first 3 hr after the disease onset. However the risk of hemorrhage and its narrow therapeutic window has limited its use in clinic. Inflammation has been known to play a crucial role in the induction and development of stroke and tumor necrosis factor-alpha (TNF-alpha) is a central player in the initiation of multiple inflammatory cascades. The recent success of three anti-TNF biologics in the clinic for the treatment of rheumatoid arthritis as well as other inflammatory diseases has further validated TNF159nflammation. TNF-alpha has also been shown to be associated with ischemic stroke. Anti-TNF biologics have been shown to be effective in reducing the disease symptoms in various pre-clinical stroke models. Small molecule TNF inhibitors are highly desirable due to the limitations of protein therapeutics. Tumor necrosis factor-alpha-converting enzyme (TACE) is the major sheddase of TNF-alpha and is essential for the generation of soluble, mature TNF-alpha. Thus TACE appears to be an attractive target for development of oral small molecule TNF-alpha inhibitors. This review summarizes the role of TNF-alpha in stroke and the effect of several TACE/MMP inhibitors in pre-clinical stroke models. The data strongly suggest that TACE/MMP inhibitors have great therapeutic potential and may be valuable alternatives in treating stroke in the clinic.
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PMID:Therapeutic potential of TACE inhibitors in stroke. 1585 1

Endothelial cells play important roles in anticoagulant and fibrinolytic systems. Recent studies suggest that increases in ambient particulate matter (PM) levels have been associated with an increase in mortality rate from cardiovascular diseases. We examined the production of heme oxygenase-1 (HO-1) and factors related to the fibrinolytic function by rat heart microvessel endothelial cells exposed to organic extracts of diesel exhaust particles (OE-DEP) and urban fine particles (OE-UFP) to investigate the direct effects of these soluble organic fractions in these PM on the fibrinolytic function of endothelial cells. The cell monolayer exposed to 10 microg/ml OE-DEP produced a larger amount of HO-1 than cells exposed to 10 microg/ml OE-UFP. OE-DEP and OE-UFP exposure reduced plasminogen activator inhibitor-1 (PAI-1) production by the cells but did not affect the production of thrombomodulin, tissue-type plasminogen activator, or urokinase-type plasminogen activator. Increased PAI-1 synthesis in response to treatment with 1.0 ng/ml tumor necrosis factor-alpha or 0.5 ng/ml transforming growth factor-beta1 was reduced by OE-DEP exposure. Suppression of PAI-1 production by OE-DEP exposure was mediated through oxidative stress and was independent of HO-1 activity. These results suggest that exposure to the soluble organic fraction of PM and DEP induced oxidative stress and reduced the PAI-1 production of endothelial cells.
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PMID:Induction of oxidative stress and inhibition of plasminogen activator inhibitor-1 production in endothelial cells following exposure to organic extracts of diesel exhaust particles and urban fine particles. 1618 11

The classic polycystic ovarian syndrome (PCOS) was originally described by Stein and Leventhal as the association of amenorrhea with polycystic ovaries and, variably, hirsutism and/or obesity. It is estimated that 5 to 10% of women of reproductive age have PCOS. Although insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS can not be denied. PCOS is associated with insulin resistance, independent of total or fat-free body mass. Postreceptor defects in the action of insulin have been described in PCOS that are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin, and thiazolidinediones (TZDs) improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that women who have PCOS have higher circulating levels of inflammatory mediators such as C-reactive protein, tumor necrosis factor, tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1). It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.
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PMID:Insulin resistance in polycystic ovarian disease. 1621 83

Vascular dysfunction, low-grade inflammation, insulin resistance, and impaired fibrinolysis have each been reported to be present in type 2 diabetes, but their relationships, and the role of obesity, have not been investigated. We measured insulin sensitivity (euglycemic clamp), forearm blood flow responses to graded local acetylcholine (Ach) and sodium nitroprusside (SNP) infusions, plasma concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, von Willebrand factor (vWF), plasminogen activator inhibitor (PAI)-1, tissue plasminogen activator (tPA), and high-sensitivity C-reactive protein (hs-CRP) in 81 diabetic patients. When patients were stratified by insulin resistance, more severe insulin resistance was associated (P < 0.05) with overweight, central fat distribution, hypertension, and dyslipidemia (with similar sex distribution, age, fasting plasma glucose, and HbA1c). With regard to vascular function, both endothelium-dependent (Ach) (-22, -40, and -52%; P < 0.0001) and -independent (SNP) (-3, -7, and -27%; P < 0.02) vasodilatation were progressively reduced across insulin resistance tertiles. In multivariate analysis, inflammatory markers (IL-6, hs-CRP, and TNF-alpha) were independently associated with insulin resistance and fasting glycemia, fibrinolytic markers PAI-1 and tPA with insulin resistance and central fat distribution, and vascular indexes (vWF, Ach, and SNP vasodilation) with insulin resistance and obesity or cytokines (TNF-alpha or IL-6). In type 2 diabetes, insulin resistance is associated with vascular dysfunction/damage, impaired fibrinolysis, and low-grade inflammation independently of obesity and poor glycemic control.
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PMID:Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes. 1656 39

The present study assessed whether tumor necrosis factor-alpha (TNFalpha) is involved in hemorrhage following large clot embolism-induced ischemia in New Zealand white rabbits by intracisternally administering either TNFalpha or a goat-anti-rabbit-TNFalpha antibody following a stroke. The first aim of the study showed that TNFalpha administration increased stroke-induced hemorrhage incidence to 53.3% from 18.5% (an increase of 188%) in the control group and also increased hemorrhage volume by 87% (p<0.05). The second aim showed that administration of tissue plasminogen activator (tPA) using a standard dose of 3.3 mg/kg increased hemorrhage incidence in rabbits to 76.5% from 18.5% (an increase of 314%) and this effect was reversed by administration of an anti-TNFalpha antibody. In the tPA-anti-TNFalpha antibody group, the absolute hemorrhage rate was 38.8% and the hemorrhage volume was 98% of control. In conclusion, following an embolic stroke, TNFalpha administration increased the incidence and volume of hemorrhage and an anti-TNFalpha antibody counteracted tPA-induced hemorrhage. The results suggest that TNFalpha may either be directly or indirectly involved in vascular damage following an embolic stroke. Moreover, TNFalpha may mediate some of the detrimental effects of tPA on the vascular compartment. Based upon our studies, TNFalpha receptor antagonists or TNFalpha processing inhibitors should be further pursued as targets for the treatment of hemorrhagic stroke as adjuvant treatment for stroke patients receiving thrombolytic treatment.
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PMID:Tumor necrosis factor-alpha is involved in thrombolytic-induced hemorrhage following embolic strokes in rabbits. 1767 88

Serglycin is a proteoglycan found in hematopoietic cells and endothelial cells. It has important functions related to formation of several types of storage granules. In connective tissue mast cells the covalently attached glycosaminoglycan is heparin, whereas mucosal mast cells and activated macrophages contain oversulfated chondroitin sulfate (type E). In mast cells, serglycin interact with histamine, chymase, tryptase and carboxypeptidase, in neutrophils with elastase, in cytotoxic T cells with granzyme B, in endothelial cells with tissue-type plasminogen activator and in macrophages with tumor necrosis factor-alpha. Serglycin is important for the retention of key inflammatory mediators inside storage granules and secretory vesicles. Serglycin can further modulate the activities of partner molecules in different ways after secretion from activated immune cells, through protection, transport, activation and interactions with substrates or target cells. Serglycin is a proteoglycan with important roles in inflammatory reactions.
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PMID:Serglycin--structure and biology. 1806 95


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