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)

Salt-loaded, spontaneously hypertensive stroke-prone rats show progressive increases in blood pressure and proteinuria and accumulate acute-phase proteins in body fluids, modeling events during renal damage. The aim of this study was to assess the pathological events occurring in the kidney of spontaneously hypertensive stroke-prone rats over time and evaluate the effects of statin treatment, which is known to improve renal and cardiovascular outcomes. Kidneys of male spontaneously hypertensive stroke-prone rats euthanized at different stages of proteinuria showed progressive inflammatory cell infiltration, the accumulation of alpha-smooth muscle actin-positive cells, degenerative changes in podocytes, and severe fibrosis. These were accompanied by an imbalance in the plasminogen/plasmin and metalloprotease systems characterized by the increased renal expression of plasminogen activator inhibitor-1, tissue plasminogen activator, and urokinase plasminogen activator; the net result was an increase in plasmin and matrix metalloproteinase (MMP)-2 and a reduction in MMP-9 activity. Chronic treatment with the hydrophilic rosuvastatin had renoprotective effects in terms of morphology and inflammation and prevented the changes in plasmin, MMP-2, and MMP-9 activity. These effects were independent of the changes in blood pressure and plasma lipid levels. Treatment with the lipophilic simvastatin was not renoprotective. These data suggest that rosuvastatin may have potential utility as a therapeutic option in renal diseases that are characterized by inflammation and fibrosis.
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PMID:Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats. 1739 57

The use of blood biomarkers is getting increasingly popular in the field of cerebrovascular diseases, since biomarkers might aid physicians in several steps of stroke evaluation. We will discuss whether stroke diagnosis might be possible using some specific brain biomarkers and if this approach will permit rapid referral of stroke patients to hospitals with acute treatments such as tissue plasminogen activator (t-PA) available. Although thrombolytic therapy in acute stroke is effective since it accelerates clot lyses and earlier restoration of blood flow, up to 40-50% of treated patients do not recanalize or do it too late, and between 6 and 15% suffer hemorrhagic transformations with high death rates. In the context of the neurovascular unit, t-PA may degrade extracellular matrix integrity and increase risks of neurovascular cell death, blood-brain barrier leakage, edema and hemorrhage. In humans, biomarkers such as matrix metalloproteinase-9 (MMP-9) or fibronectin, which might be used to select patients at higher risk of hemorrhagic transformation, and high plasminogen activator inhibitor-1 (PAI-1) interfering with tPA-induced recanalization, thus predicting clot-lyses resistance and poor outcome, have been recently identified. Moreover, high levels of MMP-9 and MMP-13 are involved in DWI lesion growth in spite of thrombolytic therapy suggesting its ultra-early role in brain injury. Other biomarkers such as C-reactive protein may accurately predict stroke mortality following reperfusion therapies. Finally, we will also show that genetic background of stroke patients may condition plasma levels of some of these biomarkers and influence therapeutic response in t-PA-treated patients.
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PMID:Stroke biomarkers: can they help us to guide stroke thrombolysis? 1722 Sep 57

Plasminogen activator inhibitor-1 (PAI-1) increases injury in several liver, lung and kidney disease models. The objective of this investigation was to assess the effect of PAI-1 deficiency on cholestatic liver fibrosis and determine PAI-1 influenced fibrogenic mechanisms. We found that PAI-1(-/-) mice had less fibrosis than wild type (WT) mice after bile duct ligation. This change correlated with increased tissue-type plasminogen activator (tPA) activity, and increased matrix metalloproteinase-9 (MMP-9), but not MMP-2 activity. Furthermore, there was increased activation of the tPA substrate hepatocyte growth factor (HGF), a known anti-fibrogenic protein. In contrast, there was no difference in hepatic urokinase plasminogen activator (uPA) or plasmin activities between PAI-1(-/-) and WT mice. There was also no difference in the level of transforming growth factor beta 1 (TGF-beta1), stellate cell activation or collagen production between WT and PAI-1(-/-) animals. In conclusion, PAI-1 deficiency reduces hepatic fibrosis after bile duct obstruction mainly through the activation of tPA and HGF.
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PMID:PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA. 1756 Oct

While recombinant tissue plasminogen activator (rt-PA) is successfully used for thrombolysis in human stroke, it may increase the risk of hemorrhagic complications. We describe the effects of different doses of rt-PA (saline, 0.9, 9, or 18 mg rt-PA/kg body weight) on the extravasation of blood components following experimental cerebral ischemia (3 h, 24 h reperfusion, suture model) in rats. The damage to the blood-brain barrier and the hemoglobin extravasation were quantified by Western blotting and immunohistochemistry. Both were significantly elevated in the ischemic cortex and basal ganglia. As rt-PA doses rose, the hemoglobin content as well as the damage to the blood-brain barrier in the ischemic side also rose significantly (p<0.001). This correlated significantly with the rising MMP-9 (matrix metalloproteinase) after increasing doses of rt-PA. Despite various benefits, rt-PA is responsible for a dose-dependent increase of edema and hemorrhage after cerebral ischemia. Clinicians should consider using the lowest effective dose of rt-PA in stroke patients.
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PMID:rt-PA causes a dose-dependent increase in the extravasation of cellular and non-cellular blood elements after focal cerebral ischemia. 1764 75

Knockout mice deficient in tissue plasminogen activator (tPA) are protected against hippocampal excitotoxicity. But it is unknown whether similar neuroprotection occurs after transient global cerebral ischemia, which is known to selectively affect the hippocampus. In this study, we tested the hypothesis that hippocampal cell death in tPA knockout mice would be reduced after transient global cerebral ischemia, and this neuroprotection would occur concomitantly with amelioration of both intra- and extracellular proteolytic cascades. Wild-type and tPA knockout mice were subjected to 20 min of transient bilateral occlusions of the common carotid arteries. Three days later, Nissl and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling staining demonstrated that hippocampal cell death was significantly reduced in tPA knockout brains compared with wild-type brains. Caspase-3 and the two major brain gelatinases (matrix metalloproteinase (MMP)-9 and MMP-2) were assessed as representative measurements of intra- and extracellular proteolysis. Post-ischemic levels of caspase-3, MMP-9 and MMP-2 were similarly reduced in tPA knockouts compared with wild-type hippocampi. Taken together, these data suggest that endogenous tPA contributes to hippocampal injury after cerebral ischemia, and these pathophysiologic pathways may involve links to aberrant activation of caspases and MMPs.
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PMID:Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia. 1793 15

Although recombinant tissue plasminogen activator (rt-PA) is successfully used for thrombolysis in human stroke, it may increase the risk of haemorrhagic complications. It was shown that the matrix metalloproteinase (MMP) system is critically involved in basal lamina degradation after middle cerebral artery occlusion and reperfusion following rt-PA administration. We describe the effects of different doses of rt-PA (saline, 0.9, 9, or 18 mg rt-PA/kg body weight) on the MMPs, their specific inhibitors (TIMPs), and also their inducer protein EMMPRIN following experimental cerebral ischemia (3 hours [h], 24 h reperfusion, suture model) in rats. The amount of MMP-2 and -9 was measured by gelatine zymography, TIMP-1 and -2 by reverse gelatine zymography, and the content of EMMPRIN and the basal lamina component collagen type IV by Western blotting. The amount of both MMPs steadily rose with increasing doses of rt-PA (p<0.05). In contrast, their endogenous inhibitors TIMPs decreased (p<0.001). A balance between the proteases and their inhibitors was achieved at the low dose of 0.9 mg/kg rt-PA in the rats, which significantly coincided with the demonstrated protection of collagen type IV degradation at this dose. The inducer protein EMMPRIN increased in parallel to its substrate MMP-2. Exogenous rt-PA leads to an increase of the MMP-inducing system by EMMPRIN, and a rise of the degrading MMPs follows. However, at low to moderate doses of rt-PA the microvascular basal lamina was protected, probably due to inhibition of MMP-2 and MMP-9 by the upregulation of their inhibitors. This strongly supports use of the lowest effective dosage of rt-PA available.
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PMID:Matrix metalloproteinase (MMP) induction and inhibition at different doses of recombinant tissue plasminogen activator following experimental stroke. 1800 May 99

The aim of the present study was to evaluate the pattern of regulation of vascular endothelial growth factor (VEGF)-A (isoforms 121, 165, 189), VEGF receptor tyrosine kinases (VEGF-R1 and VEGF-R2), matrix metalloproteinase (MMP)-1, MMP-2, MMP-14, MMP-19, tissue-specific inhibitor of metalloproteinases (TIMP)-1, TIMP-2, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) in time-defined follicle classes before (0 h) and after the application of gonadotrophin-releasing hormone (GnRH). Bovine ovaries containing periovulatory follicles or new corpora lutea (CL; Days 1-2) were collected 0, 4, 10, 20 and 25 h (follicles) or 60 h (CL) after the injection of GnRH. Transcripts of VEGF isoforms (VEGF(121), VEGF(165), VEGF(189)) were upregulated 4 h after GnRH injection (during the luteinising hormone (LH) surge) and decreased thereafter to lowest levels around ovulation. All VEGF isoforms and their receptors were upregulated again after ovulation. The VEGF peptide concentration in follicular fluid decreased 20 h after GnRH injection, followed by an increase in follicles 25 h after GnRH. Expression of MMP-1 mRNA increased rapidly 4 h after GnRH injection and remained high during the entire experimental period. In contrast, MMP-19 mRNA increased significantly only after ovulation. Expression of TIMP-1 mRNA increased 4 h after GnRH and again after ovulation. Expression of tPA mRNA increased 4 h after GnRH and remained high during the entire experimental period, whereas expression of uPA transcripts increased significantly only after ovulation. Both uPAR and PAI-1 mRNA levels increased in follicles 4 h after GnRH and again after ovulation. The amount of MMP-1 protein (immunolocalisation) increased in follicles 10 h after GnRH: additional staining was observed in the granulosa cell layer. In conclusion, the temporal and spatial pattern of regulation of VEGF and extracellular matrix-degrading proteinases during periovulation suggests they are important mediators of the LH-dependent rupture of bovine follicles and for early CL formation (angiogenesis).
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PMID:Effect of the luteinising hormone surge on regulation of vascular endothelial growth factor and extracellular matrix-degrading proteinases and their inhibitors in bovine follicles. 1825 15

Angiostrongylus cantonensis, the rat lungworm, is the principal cause of human eosinophilic meningitis or meningoencephalitis world-wide. In the present study, the efficacies of early-stage treatment with the Chinese herbal medicine long-dan-xie-gan-tan (LDXGT) and albendazole, used alone or in combination, were evaluated in BALB/c mice with A. cantonensis-induced dysfunction of the blood-central-nervous-system barrier and eosinophilic meningo-encephalitis. Indicators of the therapeutic effect included worm recovery, histopathological scores for the meningitis, assays of tissue-type plasminogen activator (PA), urokinase-type PA and matrix metalloproteinase-9 (MMP-9) in the brain, the ratio between albumin concentrations in the cerebrospinal fluid (CSF) and serum, and counts of eosinophils in the CSF. Combined treatment with albendazole and LDXGT gave better results than monotherapy based on either drug, apparently inhibiting eosinophilic meningitis via antagonists of the PA/MMP-9 system. LDXGT may have a therapeutic role in reducing inflammatory reaction in the subarachnoid space. Monotherapy with such an anti-inflammatory drug may relieve the symptoms of mild infection and the host's immune responses to A. cantonensis larvae. In severe infection, however, co-therapy with an anthelmintic (to kill the larvae) and an anti-inflammatory agent (to provide symptomatic relief) is probably a better approach. The therapeutic strategy should be tailored to the severity of the illness and the numbers of eosinophils in the CSF.
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PMID:Comparative efficacies of albendazole and the Chinese herbal medicine long-dan-xie-gan-tan, used alone or in combination, in the treatment of experimental eosinophilic meningitis induced by Angiostrongylus cantonensis. 1831 36

Hematopoietic stem cells within the bone marrow exist in a quiescent state. They can differentiate and proliferate in response to hematopoietic stress (e.g., myelosuppression), thereby ensuring a well-regulated supply of mature and immature hematopoietic cells within the circulation. However, little is known about how this stress response is coordinated. Here, we show that plasminogen (Plg), a classical fibrinolytic factor, is a key player in controlling this stress response. Deletion of Plg in mice prevented hematopoietic stem cells from entering the cell cycle and undergoing multilineage differentiation after myelosuppression, leading to the death of the mice. Activation of Plg by administration of tissue-type plasminogen activator promoted matrix metalloproteinase-mediated release of Kit ligand from stromal cells, thereby promoting hematopoietic progenitor cell proliferation and differentiation. Thus, activation of the fibrinolytic cascade is a critical step in regulating the hematopoietic stress response.
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PMID:The plasminogen fibrinolytic pathway is required for hematopoietic regeneration. 1837 7

Recombinant tissue plasminogen activator (t-PA), the only approved stroke treatment, is used for clot lysis within the occluded brain artery. Unfortunately, matrix metalloproteinase-9 (MMP-9) concentration increases after t-PA treatment and has been related to hemorrhagic transformation after ischemic stroke. Although the exact cellular source of brain MMP-9 remains unknown, invading, inflammatory cells, such as neutrophils, release MMP-9 to cross the blood brain barrier. Therefore, we hypothesize that the most feared side effect of stroke reperfusion therapy, brain hemorrhage, is related to t-PA-induced MMP-9 release by neutrophils. We show by means of ELISA that t-PA treatment promotes MMP-9, MMP-8, and tissue inhibitor metalloproteinase-2 release from human neutrophils ex vivo within 10 and 30 min. Moreover, by zymography and Western blot, we observed that neutrophils are emptied of MMP-9 content after t-PA treatment at those times. Finally, total internal reflection fluorescent imaging allowed us to observe the t-PA effect on neutrophils, showing the promotion of degranulation on these cells in vivo. Our data suggest that neutrophils are good candidates to be the main source of MMP-9 following t-PA stroke treatment and in consequence, partially responsible for thrombolysis-related brain bleedings.
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PMID:Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release. 1839 Sep 30


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