Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetic nephropathy is characterized by excessive accumulation of extracellular matrix (ECM) in the kidney. Decreased ECM degradation as well as increased ECM synthesis plays an important role in ECM remodeling that favours tissue fibrosis. Plasminogen activator (PA)/plasmin/PA inhibitor (PAI) system is involved in ECM degradation and PAI-1 plays a critical role in ECM remodeling in the kidney. Normal human kidneys do not express PAI-1 but PAI-1 is overexpressed in pathologic conditions associated with renal fibrosis including diabetic nephropathy. Reactive oxygen species mediate PAI-1 up-regulation in renal cells cultured under high glucose, hypoxia, and TGF-beta1. Recent studies utilizing PAI-1 deficient mice suggest that PAI-1 induce ECM deposition in diabetic kidney through increased ECM synthesis by TGF-beta1 up-regulation as well as through decreased ECM degradation by suppression of plasmin and MMP-2 activity.
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PMID:Plasminogen activator inhibitor-1 and diabetic nephropathy. 1617 79

Chlamydia (C.) pneumoniae are thought to infect monocytes and use them as vectors into the vessel wall, where they may accelerate atherosclerosis. We investigated the effects of C. pneumoniae on monocytic matrix metalloproteinase (MMP) activation with focus on the role of the extracellular matrix metalloproteinase inducer EMMPRIN. Human monocytes or monocytic MonoMac6 cells were infected with C. pneumoniae. Infection enhanced mRNA- and surface expression of EMMPRIN and Membrane-type-1 Matrix Metalloproteinase (MT1-MMP), plus the secretion of MMP-7, MMP-9 and the urokinase receptor (uPAR). Chlamydial heat shock protein 60 was identified to be partially responsible for EMMPRIN and MMP-9 induction, while C. trachomatis-infection had no stimulatory effect, indicating a C. pneumoniae-specific activation pathway. Suppression of EMMPRIN by gene silencing almost completely hindered the induction of MT1-MMP and MMP-9 by C. pneumoniae, suggesting a predominant regulatory role for EMMPRIN. Moreover, C. pneumoniae-infected monocytes exhibited increased MMP- and plasmin-dependent migration through "matrigel". Additionally, incubation of SMCs with supernatants of C. pneumoniae-infected monocytes induced MMP-2 activation, which was inhibited by IL1-Receptor antagonist or anti-IL-6-mAb, indicating paracrine intercellular activation pathways. In conclusion, C.pneumoniae induce MMP activity directly in monocytes through an EMMPRIN-dependent pathway and indirectly in SMCs via monocyte-derived cytokines.
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PMID:EMMPRIN (CD 147) is a central activator of extracellular matrix degradation by Chlamydia pneumoniae-infected monocytes. Implications for plaque rupture. 1654 74

Human hearts with end-stage failure and fibrosis have macrophage accumulation and elevated plasminogen activator activity. However, the mechanisms that link macrophage accumulation and plasminogen activator activity with cardiac fibrosis are unclear. We previously reported that mice with macrophage-targeted overexpression of urokinase plasminogen activator (SR-uPA+/o mice) develop cardiac macrophage accumulation by 5 weeks of age and cardiac fibrosis by 15 weeks. We used SR-uPA+/o mice to investigate mechanisms through which macrophage-expressed uPA causes cardiac macrophage accumulation and fibrosis. We hypothesized that: 1) macrophage accumulation and cardiac fibrosis in SR-uPA+/o mice are dependent on localization of uPA by the uPA receptor (uPAR); 2) activation of plasminogen by uPA and subsequent activation of transforming growth factor-beta1 (TGF-beta1) and matrix metalloproteinase (MMP)-2 and -9 by plasmin are critical pathways through which uPA-expressing macrophages accumulate in the heart and cause fibrosis; and 3) uPA-induced cardiac fibrosis can be attenuated by treatment with verapamil. To test these hypotheses, we bred the SR-uPA+/o transgene into mice deficient in either uPAR or plasminogen and measured cardiac macrophage accumulation and fibrosis. We also measured cardiac TGF-beta1 protein (total and active), Smad2 phosphorylation, and MMP activity after the onset of macrophage accumulation but before the onset of cardiac fibrosis. Finally, we treated mice with verapamil. Our studies revealed that plasminogen is necessary for uPA-induced cardiac fibrosis and macrophage accumulation but uPAR is not. We did not detect plasmin-mediated activation of TGF-beta1, MMP-2, or MMP-9 in hearts of SR-uPA+/o mice. However, verapamil treatment significantly attenuated both cardiac fibrosis and macrophage accumulation.
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PMID:Mechanisms of cardiac fibrosis induced by urokinase plasminogen activator. 1655 1

Tissue plasminogen activator (t-PA) is an extracellular serine protease that converts the proenzyme plasminogen into the broad-spectrum substrate serine protease, plasmin. Plasmin, one of the most potent pro-angiogenic factors, is a key element in fibrinolysis, cell migration, tissue remodeling and tumor invasion. In the present investigation, we assessed the impact of the truncated form of soluble melanotransferrin (sMTf) on plasminogen activation by t-PA and subsequent endothelial cell detachment. Co-treatment of human endothelial microvessel cells with plasminogen, t-PA and sMTf significantly increased plasmin formation and activity in the culture medium. Plasmin generated in the presence of sMTf also led to a 30% reduction in fibronectin detection within cell lysates and to a 9-fold increase within the corresponding cell medium. Moreover, the presence of sMTf increases EC detachment by 6-fold compared to cells treated only with plasminogen and t-PA. Although the addition of alpha(2)-antiplasmin completely prevented plasmin formation and EC detachment, epigallocatechin gallate, GM6001 and a specific antibody directed against MMP-2 prevented cellular detachment without interfering with plasminogen activation. Overall, these data suggest that the anti-angiogenic properties of sMTf may result from local overstimulation of plasminogen activation by t-PA, thus leading to subsequent degradation of the Fn matrix and EC detachment.
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PMID:Melanotransferrin stimulates t-PA-dependent activation of plasminogen in endothelial cells leading to cell detachment. 1671 48

Mechanical stimulation of the airway epithelium, as would occur during bronchoconstriction, is a potent stimulus and can activate profibrotic pathways. We used DNA microarray technology to examine gene expression in compressed normal human bronchial epithelial cells (NHBE). Compressive stress applied continuously over an 8-h period to NHBE cells led to the upregulation of several families of genes, including a family of plasminogen-related genes that were previously not known to be regulated in this system. Real-time PCR demonstrated a peak increase in gene expression of 8.0-fold for urokinase plasminogen activator (uPA), 16.2-fold for urokinase plasminogen activator receptor (uPAR), 4.2-fold for plasminogen activator inhibitor-1 (PAI-1), and 3.9-fold for tissue plasminogen activator (tPA). Compressive stress also increased uPA protein levels in the cell lysates (112.0 versus 82.0 ng/ml, P = 0.0004), and increased uPA (4.7 versus 3.3 ng/ml, P = 0.02), uPAR (1.3 versus 0.86 ng/ml, P = 0.007), and PAI-1 (50 versus 36 ng/ml, P = 0.006) protein levels in cell culture media. Functional studies demonstrated increased urokinase-dependent plasmin generation in compression-stimulated cells (0.0090 versus 0.0033 OD/min, P = 0.03). In addition, compression led to increased activation of matrix metalloproteinase (MMP)-9 and MMP-2 in a urokinase-dependent manner. In postmortem human lung tissue, we observed an increase in epithelial uPA and uPAR immunostaining in the airways of two patients who died in status asthmaticus compared with minimal immunoreactivity noted in airways from seven lung donors without asthma. Together these observations suggest an integrated response of airway epithelial cells to mechanical stimulation, acting through the plasminogen-activating system to modify the airway microenvironment.
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PMID:Induction of the plasminogen activator system by mechanical stimulation of human bronchial epithelial cells. 1679 60

The proteolytic processing of bovine fibrinogen by MMP-2 (gelatinase A), which brings about the formation of a product unable to form fibrin clots, has been studied at 37 degrees C. Catalytic parameters, although showing a somewhat lower catalytic efficiency with respect to thrombin and plasmin, indeed display values indicating a pathophysiological significance of this process. A parallel molecular modelling study predicts preferential binding of MMP-2 to the beta-chain of fibrinogen through its haemopexin-like domain, which has been directly demonstrated by the inhibitory effect in the presence of the exogenous haemopexin-like domain. However, the removal of this domain does not impair the interaction between MMP-2 and fibrinogen, but it dramatically alters the proteolytic mechanism, producing different fragmentation intermediates. The investigation at various pH values between 6.0 and 9.3 indicates a proton-linked behaviour, which is relevant for interpreting the influence on the process by environmental conditions occurring at the site of an injury. Furthermore, the action of MMP-2 on peroxynitrite-treated fibrinogen has been investigated, a situation possibly occurring under oxidative stress. The chemical alteration of fibrinogen, which has been shown to abolish its clotting activity, brings about only limited modifications of the catalytic parameters without altering the main enzymatic mechanism.
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PMID:Modulation of the proteolytic activity of matrix metalloproteinase-2 (gelatinase A) on fibrinogen. 1708 61

Tetracyclines inhibit matrix metalloproteinases (MMPs) and reduce infarction volume following cerebral ischemia. In this thesis an involvement of urokinase could be proven. Cerebral ischemia in rats was induced for 3 h followed by 24 h reperfusion (suture model). Each 6 animals received orally either doxycycline or water. Doxycycline treatment began 10 days before ischemia. MMP-2 and MMP-9 were substantially decreased. The possibility of involvement of the endogenous MMP inhibitors in the MMP inhibiting mechanisms was excluded. The plasminogen activator uPA was significantly decreased by doxycycline indicating an MMP inhibiting mechanism including the plasminogen/plasmin system. In the doxycycline group, this resulted in a decreased damage to the cerebral microvessels and less loss of the basal lamina antigen collagen type IV. Hemoglobin extravasation was also significantly reduced. Our results suggest that doxycycline may have a potential use as an anti-ischemic compound since it provides microvascular protection by inhibiting the plasminogen system.
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PMID:Doxycycline inhibits MMPs via modulation of plasminogen activators in focal cerebral ischemia. 1716 29

Matrix metalloproteinases (MMP) including MMP-2 and MMP-9 play a major role in tumour invasion by proteolysing the extracellular matrix. Their activation, particularly that of MMP-9, is partly dependent on plasmin that is inhibited by TFPI-2 (tissue factor pathway inhibitor-2), a serine protease inhibitor whose gene expression is decreased in about one-third of non-small cell lung cancers (NSCLC). In addition, MMP-2 and MMP-9 are essential in the development of NSCLC and can be regulated by functional promoter polymorphisms. In this study, the -1306C/T MMP-2, -735C/T MMP-2 and -1562C/T MMP-9 polymorphisms were analysed in 90 NSCLC patients and 90 controls. In addition, the promoter region of the TFPI-2 gene was screened for sequence variations in both groups by DHPLC. A -167G/A polymorphism was identified in 3% of controls whereas none of the 90 patients exhibited this genetic variation in the TFPI-2 promoter region. Moreover, no difference in -1306C/T MMP-2, -735C/T MMP-2 and -1562C/T MMP-9 genotypes was found between cases and controls. However, the homozygous -1562CC MMP-9 genotype was more frequent in patients with squamous cell carcinoma than in controls (p=0.018). When genotype distributions were compared to MMP-2 and MMP-9 gene expression in tumours, no relationship was found with the -1306 MMP-2 and -1562 MMP-9 polymorphisms. In contrast, tumour MMP-2 gene expression was lower in homozygous -735CC patients than in those with CT or TT genotypes. In addition, the survival time was longer in patients with the MMP-2 -735T allele than in those with the CC genotype (p=0.02). The relative risk of death was increased 2.6-fold in -735CC patients (p=0.045; 95% CI=1.0-6.7). The results of this study suggest that the -735C/T MMP-2 polymorphism might be an independent prognostic marker in NSCLC, but this should be confirmed in a larger cohort of patients.
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PMID:Influence of MMP-2 and MMP-9 promoter polymorphisms on gene expression and clinical outcome of non-small cell lung cancer. 1720 28

The remodelling of extracellular matrix and angiogenesis represent two essential processes for tumor growth and metastatic dissemination. These phenomena imply many interactions between tumor cells and host cells via action of various proteases including metalloproteinases (MMPs) whose activity is controlled by TIMPs and serine proteases (tissue type Plasminogen Activator (tPA), urokinase type Plasminogen Activator (uPA) and plasmin) inhibited in particular by PAI-1 (Plasminogen Activator Inhibitor- 1). Evolution of tumors depends on the joint action of these enzymes, as well as precise balance between these proteases and their physiological inhibitors. Proteases regulate the fate and activity of many proteins by controlling appropriate intra- or extracellular localization; shedding from cell surfaces ; activation or inactivation of proteases and other enzymes, cytokines, hormones or growth factors and exposure of cryptic neoproteins. Hence, proteases initiate, modulate and terminate a wide range of important cellular functions by processing bioactive molecules an thereby control essential biological processes, such as DNA replication, cell-cycle progression, cell proliferation, differentiation and migration, morphogenesis and tissue remodelling, neuronal outgrowth, haemostasis, wound healing, immunity, angiogenesis and apoptosis. Work completed has for objective to elucidate the specific part played by serine proteases and MMPS produced by the host cells in the processes of tumor growth and angiogenesis. By using an original model of transplantation of malignant murine keratinocytes (PDVA cell line) into deficient mice (-/-) and wild type mice (+/+), we showed the essential proteolytic role of PAI-1 produced by host cells in the tumor progression and angiogenesis. This mechanism of PAI-1 action was confirmed by using the model in vitro aorta rings. By using deficient mice for one or two MMPs combined (MMP-2, MMP-3, MMP-9, MMP-11, MMP-2&9, MMP3&9), we demonstrated that only the combined deficiency of MMP-2 and -9 showed an absence of tumor invasion and angiogenesis. These data suggest the existence of compensatory mechanisms of a MMP by another MMP or another proteolytic way. These phenomena of redundancy are to be known and detailed to elaborate in a near future, the development of specific inhibitors of MMPS.
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PMID:[Roles of serine proteases and matrix metalloproteinases in tumor invasion and angiogenesis]. 1728 5

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


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