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)

Plasmin, the enzymatically active form of plasminogen, can activate several matrix metalloproteinases (MMPs). In this study, we investigated the activation of MMP-1, one of the major interstitial collagenases, by plasmin which was generated on the surface of Staphylococcus aureus cells. Plasmin bound to plasminogen receptors on S. aureus degraded the major (125)I-labeled 55-kDa proMMP-1 into the 42-kDa form corresponding to the size of active MMP-1. MMP-1 formed by S. aureus-bound plasmin was also enzymatically active as judged by digestion of the synthetic collagenase substrate, DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH(2). The finding that, in MMP-1 molecules generated either by soluble plasmin or by S. aureus-bound plasmin, the amino-terminal amino acid sequences were identical indicated that the activation mechanisms of the two plasmin forms do not differ from each other. The present observations emphasise and broaden the physiological importance of bacterial plasminogen receptors. In addition to direct proteolytic effects on components of the extracellular matrix, receptor-bound plasmin is also capable of initiating an MMP-1-dependent matrix-degrading enzymatic cascade.
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PMID:Activation of interstitial collagenase, MMP-1, by Staphylococcus aureus cells having surface-bound plasmin: a novel role of plasminogen receptors of bacteria. 1056 88

We examined the role of the serine proteinase plasmin in regulating fibroblast-mediated tissue remodeling during wound healing. As an in vitro model system, collagen lattices were seeded with human dermal fibroblasts, and various concentrations of plasmin were added to the medium of the contracting lattices. Within 16 h, fibroblast-populated collagen lattices treated with plasmin rapidly contracted from approximately 20 mm to less than 2 mm in diameter. Measurements of collagen lattices with radiolabeled collagen indicated that, when these lattices included either fibroblasts or conditioned medium derived from fibroblast-populated collagen lattices, exogenous plasmin induced collagen degradation and rapid lattice contraction. Western blot analyses of conditioned medium demonstrated that fibroblasts in collagen lattices secreted the latent matrix metalloproteinase, MMP-1, which was subsequently cleaved by plasmin. Additionally, rapidlattice contraction and collagen degradation were blocked when collagen lattices were treated simultaneously with plasmin and aprotinin or a tissue inhibitor of metalloproteinases, TIMP-1. These results provide strong evidence that plasmin regulates rapid contraction of collagen lattices by activating fibroblast-secreted MMP-1 that triggers collagen degradation. The findings from this study suggest that fibroblast-populated collagen lattices can be used as an in vitro model system to investigate the mechanisms by which plasmin and cell-secreted plasminogen activators control MMP-1 mediated extracellular lattice degradation and remodeling during wound healing.
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PMID:Plasmin triggers rapid contraction and degradation of fibroblast-populated collagen lattices. 1073 68

We have established that treatment of cultured human skin fibroblasts with tropoelastin or with heterogenic peptides, obtained after organo-alkaline or leukocyte elastase hydrolysis of insoluble elastin, induces a high expression of pro-collagenase-1 (pro-matrix metalloproteinase-1 (pro-MMP-1)). The identical effect was achieved after stimulation with a VGVAPG synthetic peptide, reflecting the elastin-derived domain known to bind to the 67-kDa elastin-binding protein. This clearly indicated involvement of this receptor in the described phenomenon. This notion was further reinforced by the fact that elastin peptides-dependent MMP-1 up-regulation has not been demonstrated in cultures preincubated with 1 mm lactose, which causes shedding of the elastin-binding protein and with pertussis toxin, which blocks the elastin-binding protein-dependent signaling pathway involving G protein, phospholipase C, and protein kinase C. Moreover, we demonstrated that diverse peptides maintaining GXXPG sequences can also induce similar cellular effects as a "principal" VGVAPG ligand of the elastin receptor. Results of our biophysical studies suggest that this peculiar consensus sequence stabilizes a type VIII beta-turn in several similar, but not identical, peptides that maintain a sufficient conformation to be recognized by the elastin receptor. We have also established that GXXPG elastin-derived peptides, in addition to pro-MMP-1, cause up-regulation of pro-matrix metalloproteinase-3 (pro-stromelysin 1). Furthermore, we found that the presence of plasmin in the culture medium activated these MMP proenzymes, leading to a consequent degradation of collagen substrate. Our results may be, therefore, relevant to pathobiology of inflammation, in which elastin-derived peptides bearing the GXXPG conformation (created after leukocyte-dependent proteolysis) bind to the elastin receptor of local fibroblasts and trigger signals leading to expression and activation of MMP-1 and MMP-3, which in turn exacerbate local connective tissue damage.
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PMID:Conformational dependence of collagenase (matrix metalloproteinase-1) up-regulation by elastin peptides in cultured fibroblasts. 1108 20

Borrelia burgdorferi, the spirochetal agent of Lyme disease, stimulated human peripheral blood monocytes to release pro-matrix metalloproteinase-9 (gelatinase B; pro-MMP-9) and active matrix metalloproteinase-1 (collagenase-1; MMP-1). Human neutrophils also released pro-MMP-9 and a 130-kDa protein with gelatinolytic activity in response to live B. burgdorferi. In addition, U937 cells and human keratinocyte cells were also stimulated to release pro-MMP-9 under the same conditions. However, human umbilical vein endothelial cells (HUVECs) released pro-MMP-9 and pro-MMP-2 in a constitutive manner and were not influenced by live spirochetes. MMPs produced by human monocytes also enhanced the penetration of B. burgdorferi through extracellular matrix component barriers in vitro. Plasmin stabilized on the surface of the Lyme disease spirochete was shown to activate pro-MMP-9 to its active form. This active form was also observed in the plasma of mice infected with a relapsing fever borrelia. These results suggest that borreliae can upregulate MMPs and possibly mediate an activation cascade initiated by plasmin bound to the microbial surface. MMPs may play a role in dissemination of the Lyme disease spirochete and in the pathogenesis of Borrelia infection.
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PMID:Borrelia spirochetes upregulate release and activation of matrix metalloproteinase gelatinase B (MMP-9) and collagenase 1 (MMP-1) in human cells. 1111 37

Here, we describe a new function for plasmin and matrix metalloproteinases (MMPs), which is to regulate the regression of capillary tubes in three-dimensional extracellular matrix environments. Using a well-described capillary morphogenesis system in three-dimensional collagen matrices, a new model of capillary regression has been established by adding plasminogen to the culture medium. Plasminogen is converted to plasmin by endothelial cell plasminogen activators which then induces matrix metalloproteinase-dependent collagen gel contraction and capillary regression. Plasminogen addition results in activation of MMP-1 and MMP-9, which then results in collagen proteolysis followed by capillary regression. The endothelial cells undergo apoptosis following gel contraction as detected by flow cytometric analysis as well as by detectable caspase-3 cleavage and caspase-dependent cleavage of the actin cytoskeletal regulatory protein, gelsolin. In addition, directly correlating with the contraction response, tyrosine phosphorylation of p130cas, an adapter protein in the focal adhesion complex, is observed followed by disappearance of the protein. Proteinase inhibitors that block MMPs (TIMP-1 or TIMP-2), plasminogen activators (PAI-1) or plasmin (aprotinin) completely block the gel contraction and regression process. In addition, chemical inhibitors of MMPs that block capillary regression also block MMP-1 and MMP-9 activation suggesting that a key element in this regression response is the molecular control of MMP activation by endothelial cells. Blocking antibodies directed to MMP-1 or MMP-9 interfere with capillary regression while blocking antibodies directed to PAI-1 accelerate capillary regression suggesting that endogenous synthesis of PAI-1 negatively regulates this process. These data present a novel system to study a new mechanism that may regulate regression of capillary tubes, namely, plasmin and MMP-mediated degradation of extracellular matrix.
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PMID:Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. 1118 Nov 75

Matrix metalloproteinases (MMP) responsible for degradation of connective tissue are found in most tissues. The MMP are regulated at the levels of transcription, zymogen activation by plasmin or membrane-type- (MT) MMP, and control of enzyme activity by tissue inhibitors of metalloproteinases (TIMP). Whole bovine skeletal muscle showed multiple MMP activities on gelatin zymography and also expressed mRNA encoding MMP-1, -2, -9, -14, and -16, tissue inhibitors of metalloproteinase (TIMP)-1, -2, and -3 and plasminogen activator and its receptor. Purified intramuscular fibroblasts and myogenic cell culture derived from satellite cells expressed most or all of these elements. Statistical analysis (n = 35) revealed a strong positive correlation among the mRNA levels of several elements of the MMP system, including MMP-2, MMP-14, TIMP-1, -2, and -3 (r = 0.614 to 0.930, P < 0.0001). Our results provide an extensive profile of an extracellular proteolytic cascade involving MMP in skeletal muscle and suggest that 1) the activation cascades of muscle MMP may be initiated by both plasmin and membrane-type MMP; 2) a group of genes involved in the same "arm" of zymogen activation are coexpressed in this tissue; and 3) skeletal muscle cells, in addition to the intramuscular fibroblasts, express an extensive complement of MMP and related proteins.
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PMID:Coordinate expression of matrix-degrading proteinases and their activators and inhibitors in bovine skeletal muscle. 1120 21

The plasma fibrinolytic/proteolytic balance was assessed in 60 stable angina patients who underwent control coronary catheterization and the results were correlated with angiographic findings and control samples (n = 20). The concentrations of t-PA, PAI-1, collagenase (MMP-1), tissue inhibitor of MMP (TIMP-1), plasmin-antiplasmin (PAP) complexes and alpha2-macroglobulin (alpha2-M) were measured in plasma samples. The results showed a significant increase of PAP (p <0.001) and a reduction of alpha2-M (p <0.001) in the group of patients when compared to controls, indicating a degree of fibrinolysis/proteolysis activation. There was no correlation between the different parameters analyzed and the extent of angiographically proven atherosclerosis (one or more stenotic vessels), while the t-PA levels were significantly elevated (p <0.03) in patients with coronary stenosis > or =75% or occlusion. We conclude that there is a disturbance of the plasma fibrinolysis/proteolysis in patients with stable angina not related to the extent of atherosclerosis. The t-PA levels may be a good marker for coronary occlusion in these patients.
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PMID:Fibrinolysis/proteolysis balance in stable angina pectoris in relation to angiographic findings. 1152 15

During melanoma progression, migrating cells must cross human dermis, a type I collagen-rich tissue. We have show that MMP-1 and MMP-2 act in a cumulative manner in the in vitro invasion of a three-dimensional type I collagen matrix by melanoma cells. Two melanoma cell lines (M1Dor and M3Da) previously reported to secrete proMMP-2 in a direct relationship with their tumorigenic potential into nude mice were used (F. Capon et al., 1999, Clin. Exp. Metastasis 17, 463-469). The highly tumorigenic cell line (M3Da) displayed a five-fold faster migration rate in type I collagen matrix, compared to its lower tumorigenic counterpart (M1Dor). In parallel, activation of proMMP-2 was evidenced in M3Da- but not M1Dor-populated collagen lattices. Such enzyme activation was associated with a significant decrease in TIMP-2 and TIMP-1 production. Agents known to interfere with proMMP-2 activation, i.e., excess TIMP-2, furin convertase inhibitor, and alphavbeta3 blocking antibody, reduced by 30-40% the type I collagen invasive capacity of M3Da cells. By comparison, batimastat, a wide-spectrum MMP inhibitor, exhibited a more pronounced inhibitory effect (>70%). It suggested that other collagenases than MMP-2 could participate in type I collagen invasion. Collagenase-3 (MMP-13) was produced at low levels by melanoma cells whatever the cell culture conditions. In contrast, M3Da and M1Dor cells secreted collagenase-1 (MMP-1) following 48 h of culture on plastic dishes. Growing melanoma cells in type I collagen gel did not modify enzyme production, but induced proMMP-1 activation in M3Da but not M1Dor cell-populated lattices. Blocking the plasmin-mediated proMMP-1 activation by aprotinin inhibited type I collagen gel invasion by 30%. Since the combination of aprotinin and furin convertase inhibitor reduced collagen invasiveness by melanoma cells to a level comparable to that attained with batimastat, we conclude that both MMP-2 and MMP-1 are involved in such tissue invasion.
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PMID:Cumulative influence of matrix metalloproteinase-1 and -2 in the migration of melanoma cells within three-dimensional type I collagen lattices. 1159 33

Cells of the monocyte/macrophage lineage are involved in the development of inflammatory joint diseases such as rheumatoid arthritis. This disease is characterized by cartilage degradation and synovial membrane inflammation with a progressive loss of joint function. The pathological processes are still not well understood. Therefore it would be interesting to develop a suitable experimental in vitro model system for defined studies of monocyte/macrophage and chondrocyte interactions at the molecular level. For that purpose we cocultured chondrocytes from adult human articular cartilage with human monocytes and macrophages for defined periods of time in agarose without addition of serum. We performed zymographic and western blot analysis of culture medium, completed by quantitative RT-PCR of each chondrocyte, monocyte and macrophage RNA, respectively. The reliability of the newly established coculture systems is confirmed by causing a clear decrease of intact aggrecan in the coculture medium plus concurrent appearance of additional smaller fragments and a reduction of chondrocyte aggrecan and collagen II gene expression in the presence of monocytes. In culture medium from cocultures we detected active forms of the matrix metalloproteinases MMP-1, MMP-3 and MMP-9 accompanied by induction of gene expression of MMP-1, membrane type 1 MMP (MT1-MMP) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in chondrocytes. No gene expression of MMP-9 was detectable in chondrocytes, the enzyme was solely expressed in monocytes and macrophages and was downregulated in the presence of chondrocytes. Our results suggest that MMP-9 protein in coculture medium originated from monocytes and macrophages but activation required chondrocyte-derived factors. Because addition of plasmin, a partial activator of pro-MMP-3 and pro-MMP-1, enhanced the activation of pro-MMP-9 and pro-MMP-1 in cocultures but not in monocultured macrophages, and the presence of MMP-3 inhibitor II prevented pro-MMP-9 activation, we assumed a stepwise activation process of pro-MMP-9 that is dependent on the presence of at least MMP-3 and possibly also MMP-1.
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PMID:Paracrine interactions of chondrocytes and macrophages in cartilage degradation: articular chondrocytes provide factors that activate macrophage-derived pro-gelatinase B (pro-MMP-9). 1171 48

We investigated the kinetics of matrix metalloproteinases (MMPs) and their regulatory factors mRNAs in the kidneys of mercuric chloride-treated Brown Norway rats. The expression of MMP-1 mRNA remained at lower levels than control, while other MMPs mRNAs were upregulated. The expression of tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA showed significant upregulation. On the other hand, the expressions of TIMP-2 and TIMP-3 mRNAs were not significantly changed. In the plasmin-dependent pathway, the expression of plasminogen activator inhibitor (PAI-1) mRNA was continuously increased, while the expression of urokinase-type plasminogen activator (uPA) mRNA was not increased. The signals of TIMP-1 and PAI-1 mRNAs examined by in situ hybridization, were localized in the regenerative epithelial cells of the proximal tubules. In conclusion, these findings suggest that the activity of MMPs may bealtered by MMP-1 downregulation and inhibition of MMP activity by PAl-1 and TIMP-1 generated from tubular epithelial cells.
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PMID:Kinetics of matrix metalloproteinases and their regulatory factors in mercuric chloride-induced tubulointerstitial fibrosis in Brown Norway rats. 1181 2


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