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)

Cultured cells grown as spheroids provide an in vitro model that is closer to an in vivo tumour than conventional monolayer techniques. Previous work from our laboratory has demonstrated that spheroids formed from multidrug-resistant MCF-7 cells exhibit invasive characteristics which were not present in their sensitive counterparts. The treatment of these spheroids by all-trans-retinoic acid (ATRA), a potent inducer of in vitro and in vivo differentiation, decreases their proteolytic activity and ability to invade Matrigel-coated filters. The efficiency of ATRA is enhanced by its incorporation into low-density lipoprotein (LDL) (LDL-ATRA). Indeed, invasion through a reconstituted basement membrane was reduced by 73% with 10(-6) M ATRA and 3 x 10(-8) M LDL-ATRA. Furthermore, inhibition of invasion was correlated with a decrease in several factors: (1) secreted matrix metalloproteinase-9 and enzymes degrading type IV collagen and Matrigel films, and (2) tissue plasminogen activator. The results observed were found with a concentration of LDL-ATRA 30 times lower than that of ATRA. This could be due to the protective effect of LDL and to a better targeting of cancer cells through their LDL receptors. LDL-ATRA may therefore represent a new and potent inhibitor of invasion that could be developed for clinical trials.
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PMID:Effects of all-trans-retinoic acid incorporated into low-density lipoprotein on invasive properties of multidrug-resistant MCF-7 spheroids. 1072 68

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

The primary role of cigarette smoking in the development of coronary heart disease is to cause damage to the vascular endothelium, leading to endothelial cell dysfunction and initiating the pathogenesis of coronary atherosclerosis. We studied the response of human coronary artery endothelial cells to nicotine exposure by examining the expression of a panel of genes encoding molecules that have been shown to be involved in atherogenesis. Treatment of primary human coronary artery endothelial cells with nicotine for 24 h at concentrations (10(-5) and 10(-7) M) similar to those in the blood of smokers resulted in increased mRNA levels of endothelial nitric oxide synthase, angiotensin-I converting enzyme, tissue-type plasminogen activator, plasminogen activator inhibitor-1, von Willebrand factor, and vascular cell adhesion molecule-1. No change was detected in the expression levels of the genes encoding basic fibroblast growth factor, endothelin-1, endothelial leukocyte adhesion molecule-1 and matrix metalloproteinase-2 under these conditions. These data indicate that nicotine alters the expression of a number of endothelial genes whose products play major roles in regulating the vascular tone and thrombogenicity, making a contribution to the understanding of the effects of cigarette smoking on the development of coronary atherosclerosis.
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PMID:Nicotine induced changes in gene expression by human coronary artery endothelial cells. 1116 59

Many theories propose that sleep serves a purpose in synaptic plasticity. We tested the hypothesis, therefore, that manipulation of sleep would affect the expression of molecules known to be involved in synaptic plasticity. mRNA expression of four molecules [brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeleton-associated protein (Arc), matrix metalloproteinase-9 (MMP-9), and tissue plasminogen activator (tPA)] was determined after 8 h of sleep deprivation and after 6 h of a mild increase in ambient temperature, a condition that enhances sleep in rats. After sleep deprivation, BDNF, Arc, and tPA mRNAs in the cerebral cortex increased while MMP-9 mRNA levels decreased. Conversely, after enhanced ambient temperature, BDNF, Arc, and tPA mRNAs decreased while MMP-9 mRNA increased. In the hippocampus, sleep deprivation did not significantly affect BDNF and tPA expression, although Arc mRNA increased and MMP-9 mRNA decreased. Brain temperature enhancement decreased Arc mRNA levels in the hippocampus but did not affect BDNF, MMP-9, or tPA in this area. Results are consistent with the notion that sleep plays a role in synaptic plasticity.
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PMID:Conditions that affect sleep alter the expression of molecules associated with synaptic plasticity. 1150 99

Plasminogen can be converted to plasmin either via the tissue-type plasminogen activator (t-PA) or via the urokinase-type plasminogen activator (u-PA)/u-PA receptor (u-PAR) pathway. A dual role for these pathways is now well established: 1) t-PA is involved in fibrin homeostasis and 2) u-PA is primarily involved in cell migration and tissue remodeling. t-PA mediated activation is used for thrombolytic therapy of acute myocardial infarction and some other thromboembolic diseases. The u-PA mediated pathway, in concert with the matrix metalloproteinase (MMP) system, plays a pleiotropic role in arterial neointima formation, atherosclerosis, angiogenesis, tumor growth metastasis, and infarction. However, therapeutic interventions in the u-PA/MMP system remain to be further defined.
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PMID:Ham-Wasserman lecture: role of the plasminogen system in fibrin-homeostasis and tissue remodeling. 1172 75

Plasminogen activators (PAs) and matrix metalloproteinases (MMPs) are considered to play an important role in the pathogenesis of multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is widely used as an animal model of multiple sclerosis. Whereas several studies have addressed the expression of various MMPs and their inhibitors in the pathogenesis of EAE, the expression of the molecules of the PA system during EAE has not been reported previously. The present study was undertaken to investigate the expression of the molecules of the PA system (tPA, uPA, PAI-1, uPAR, LRP), as well as several members of the MMP family and their inhibitors in the course of actively induced EAE in BALB/c mice. During clinical EAE, the PA system was up-regulated in the central nervous system at several levels. Induction of expression of tPA and PAI-1 transcripts was detected in activated astrocytes in the white matter. Inflammatory cells expressed uPA receptor, uPAR. In situ zymography demonstrated the presence of increased tPA and uPA activities in the areas of the inflammatory damage. Accumulation of fibrin, fibronectin, and vitronectin immunoreactivity was seen in perivascular matrices of symptomatic animals. In addition, transcription of MT1-MMP and metalloelastase (in inflammatory cells), and TIMP-1 (in activated astrocytes) was induced during EAE. Increased gelatinolytic activity was detected at the sites of inflammatory cell accumulation by in situ zymography of fluorescently labeled gelatin; substrate gel zymography identified the up-regulated gelatinolytic activity as gelatinase B. Overall, our study demonstrates concurrent induction of PA and MMP systems during active EAE, supporting further the concept that the neuroinflammatory damage in EAE involves altered balance between multiple extracellular proteases and their inhibitors.
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PMID:Coordinated induction of extracellular proteolysis systems during experimental autoimmune encephalomyelitis in mice. 1173 72

Previously, we demonstrated that amorphous calcium phosphate (ACP), chemical precursor to apatite, strongly interacted with fibrin and facilitated binding of matrix metalloproteinase (MMP)-9, a type IV collagenase. Plasmin-dependent fibrinolysis resulted in coordinate MMP-9 activation. Here we report on the effect(s) of ACP on fibrin degradation and binding of endogenous plasma proteases. Electrophoresis (8.5% SDS-PAGE) revealed that fibrin formed in the presence of ACP demonstrated characteristic gamma-gamma dimers (90-kDa) and beta-monomers (55-kDa), but resisted spontaneous fibrinolysis (72 h, 37 degrees C) or degradation by plasminogen activators (uPA, tPA). Casein zymography revealed an ACP-dependent decrease in fibrin binding of a low molecular weight (Mw) protease triplet (47-, 43-, 42-kDa) and increased fibrin binding of two high Mw proteases (94- and 84-kDa). The low Mw triplet also possessed gelatinolytic activity, but was not an MMP since 1,10-phenanthroline was ineffective as an inhibitor. Fibrin-binding proteases were inhibited to some degree by the serine protease inhibitor aprotinin. Competition/dissociation experiments with epsilon-aminocaproic acid revealed that the low Mw triplet lacked kringle regions whereas the 94- and 84-kDa proteases were tentatively identified and glu-/lys-plasmin(ogen)s. The triplet may, however, represent one or more kringle deficient mini-plasminogen(s), since electrophoretic mobility and substrate specificity was similar to elastase-generated mini-plasminogen. To explore these findings in a clinically relevant setting, a series of plasma samples was collected from a patient with unstable angina prior to, during, and post coronary artery bypass graft (CABG) surgery. Fibrin formed from plasma collected during and immediately post CABG was associated with increased fibrinolytic capacity and enhanced binding of a) MMP-9, b) the low Mw protease triplet (described above), and c) PA (as putative 110-kDa tPA:PAI-1 complex). The relevance of these findings to pathologic calcification of atherosclerotic plaques is discussed.
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PMID:Interaction of amorphous calcium phosphate with fibrin in vitro causes decreased fibrinolysis and altered protease profiles: implications for atherosclerotic disease. 1182 Apr 59

Several matrix metalloproteinases (MMPs), including the stromelysins MMP-3 and MMP-11, are expressed in adipose tissue. To investigate a potential role of MMP-11 (stromelysin-3) in adipose tissue development, five-week-old male wild-type mice (MMP-11+/+) or mice with deficiency of MMP-11 (MMP-11-/-) were fed a high fat diet (HFD, 42% fat) for 15 weeks. Haematologic parameters, including white and red blood cells, platelets, haemoglobin and haematocrit, and metabolic parameters including glucose, triglycerides and total cholesterol were not different for both genotypes. At the time of sacrifice, the body weight of the MMP-11-/- mice was higher than that of the MMP-11+/+ mice (36+/-1.4 g versus 29+/-0.9 g, p = 0.0002). The weight of the isolated subcutaneous (SC) and gonadal (GON) fat deposits was also higher in MMP-11-/- mice (620+/-150 mg versus 280+/-28 mg for SC fat, and 970+/-180 mg versus 430+/-62 mg, p < 0.05, for GON fat). Adipocytes in MMP-11-/- adipose tissue were hypertrophic as compared to MMP-11+/+ adipocytes (volume of 57+/-12 x 10(3) microm3 versus 31+/-2.4 x 10(3) microm3 for SC fat, and 100+/-18 x 10(3) microm3 versus 57+/-7.6 x 10(3) microm3 for GON fat; both p < 0.06). In nutritionally induced obesity models in mice a potential role of the fibrinolytic system was suggested in adipocyte hypertrophy. The hypertrophy observed in this model is, however, not related to changes in fibrinolytic parameters, as suggested by our finding that levels of t-PA, u-PA and PAI-1 antigen as well as t-PA and u-PA activity were not different in SC or GON adipose tissue extracts of both genotypes. As the main biological function of MMP-11 remains unknown, it is not clear whether the adipocyte hypertrophy in MMP-11-/- adipose tissue is directly related to the deficiency or to other pathways affected by MMP-11.
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PMID:Adipocyte hypertrophy in stromelysin-3 deficient mice with nutritionally induced obesity. 1191 87

AE-941 (Neovastat) is a naturally occurring product extracted from cartilage and has antiangiogenic properties. It has reached Phase III clinical trial evaluation for the treatment of solid tumors (non-small cell lung cancer and renal cell carcinoma) and a pivotal Phase II clinical trial in multiple myeloma is ongoing. AE-941 inhibits several steps of the angiogenesis process, including matrix metalloproteinase activities and VEGF signaling pathways. Moreover, AE-941 induces endothelial cell apoptosis and tissue-type plasminogen activator activity, thus suggesting that it is a multifunctional antiangiogenic drug. Results from Phase I/II clinical trials indicate that AE-941, given orally, is well tolerated. Moreover, the median survival time in patients with renal cell carcinoma and non-small cell lung cancer was significantly longer in patients receiving high doses of AE-941 compared to low doses.
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PMID:AE-941 (Neovastat): a novel multifunctional antiangiogenic compound. 1211 1

Matrix metalloproteinase-14 is required for degradation of fibrillar collagen by mesenchymal cells. Here we show that keratinocytes use an alternative plasminogen and matrix metalloproteinase-13-dependent pathway for dissolution of collagen fibrils. Primary keratinocytes displayed an absolute requirement for serum to dissolve collagen. Dissolution of collagen was abolished in plasminogen-depleted serum and could be restored by the exogenous addition of plasminogen. Both plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase blocked collagen dissolution, demonstrating the requirement of both plasminogen activation and matrix metalloproteinase activity for degradation. Cell surface plasmin activity was critical for the degradation process as aprotinin, but not alpha(2)-antiplasmin, prevented collagen dissolution. Keratinocytes with single deficiencies in either urokinase or tissue plasminogen activator retained the ability to dissolve collagen. However, collagen fibril dissolution was abolished in keratinocytes with a combined deficiency in both urokinase and tissue plasminogen activator. Combined, but not single, urokinase and tissue plasminogen activator deficiency also completely blocked the activation of the fibrillar collagenase, matrix metalloproteinase-13, by keratinocytes. The activation of matrix metalloproteinase-13 in normal keratinocytes was prevented by plasminogen activator inhibitor-1 and aprotinin but not by tissue inhibitor of metalloproteinase-1 and -2, suggesting that plasmin activates matrix metalloproteinase-13 directly. We propose that plasminogen activation facilitates keratinocyte-mediated collagen breakdown via the direct activation of matrix metalloproteinase-13 and possibly other fibrillar collagenases.
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PMID:Collagen dissolution by keratinocytes requires cell surface plasminogen activation and matrix metalloproteinase activity. 1219 5


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