Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerotic lesions contain macrophages, smooth muscle cells and endothelial cells, all of which participate in lesion development. Upon stimulation these cells express a variety of different factors and receptors which are involved in lipid metabolism, cellular proliferation, tissue repair, immune response and inflammatory reactions. During the last few years, active expression of several genes has been reported in developing atherosclerotic lesions. These genes include scavenger receptor, 15-lipoxygenase, monocyte chemoattractant protein-1, macrophage colony stimulating factor-1, lipoprotein lipase, platelet-derived growth factor, tissue factor, apolipoprotein E, stromelysin, different adhesion molecules and various cytokines. Evidence continues to grow that the pattern of gene expression and the functional status of cells in different regions of atherosclerotic lesions may differ considerably and could be regulated by local factors present in atherosclerotic lesions. One such a powerful factor which may contribute to the regulation of gene expression in developing lesions is oxidized LDL which has been shown to affect the expression of cytokines, growth factors and chemotactic factors by arterial cells. Recent developments in the analysis of gene expression in the artery wall at the cellular level will undoubtedly increase our understanding about the sequence of events leading to the formation of atherosclerotic lesions.
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PMID:Gene expression in atherosclerotic lesions. 147 13

Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis that stimulates proliferation, migration, and proteolytic activity of endothelial cells. Although the mitogenic activity of VEGF is endothelial cell specific, recent reports indicate VEGF is able to stimulate chemotaxis and tissue factor production in monocytes. VEGF-stimulated activity in monocytes is mediated by the VEGF receptor flt-1. The purpose of the present study was to investigate the effects of VEGF on another major cell type in the vascular wall, namely, the vascular smooth muscle cell (SMC). Using cultured cells, we showed that VEGF has a minimal mitogenic effect on SMCs, which is in accordance with published data. However, VEGF treatment significantly enhanced production of matrix metalloproteinase (MMP)-1, -3, and -9 by human SMCs. The upregulation of MMP-1 and MMP-9 was pronounced, and the stimulation for MMP-3 was less prominent. Stimulation could be demonstrated at both protein and mRNA levels, as reflected by ELISA, zymography, and Northern blot analysis. To explore the signal transduction pathway for the effect of VEGF on SMCs, we studied the expression of 2 high-affinity VEGF receptors, the kinase insert domain-containing receptor (KDR) and flt-1, in human SMCs. Both reverse transcriptase-polymerase chain reaction and immunoblotting revealed the expression of flt-1. Immunoprecipitation followed by immunoblotting illustrated phosphorylation of the flt-1 receptor after VEGF treatment. Similar methodology failed to detect expression of KDR in human SMCs. These data suggest the role of flt-1 in mediating VEGF-stimulated MMP expression of SMCs. The physiological relevance of MMP upregulation was studied by examining VEGF-stimulated SMC migration through 2 synthetic extracellular matrix barriers, Matrigel and Vitrogen. Our results indicate that VEGF treatment accelerated SMC migration through both barriers, and that this response was blocked by MMP inhibition in Matrigel, which supports a permissive role of MMP in SMC migration. These data are the first to show a direct effect of VEGF on SMCs. SMC-derived MMPs may be an additional source of proteases to digest vascular basement membrane, which is a crucial step in the initial stage of angiogenesis. The MMPs may also contribute to SMC migration in angiogenesis and atherogenesis.
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PMID:Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: role of flt-1. 977 30

The abortifacient and menstrual effects of the potent antiprogestin, RU 486 (mifepriston) are associated with both endometrial hemorrhage and extracellular matrix (ECM) degradation. Such processes reflect reduced perivascular decidual cell hemostatic and increased ECM-degrading protease activity. In this review, we summarize the effects of RU 486 on different proteases involved in these processes and expressed by in vitro decidualized endometrium stromal cells. The expression of tissue factor (TF), the primary initiator of hemostasis; urokinase-type plasminogen activator (uPA); tissue-type plasminogen activator (tPA); plasminogen activator inhibitor-1 (PAI-1) as well as the potent matrix metalloprotease, MMP-3 was assessed. These endpoints of decidualization are regulated by progesterone. It was observed, that RU 486 blocks and reverses progestin-enhanced stromal cell TF protein and mRNA expression and PAI-1 protein and mRNA expression, whereas blocks and reverses progestin-inhibited stromal cell uPA, tPA and MMP-3 protein and mRNA expression. These coordinate enhancement of plasminogen activator and MMP-3 expression promotes proteolysis of the decidual ECM, which leads to endometrial sloughing during menstruation. Moreover, destabilization of endometrial microvessels resulting from degradation of their surrounding ECM is consistent with the heavy bleeding after RU 486 administration. On the other hand, with blocking the expression of TF and PAI-1, RU 486 creates a haemorrhagic and fibrinolytic milieu around the endometrial vessels, suggesting a mechanism for RU 486-induced endometrial hemorrhage. The steroid antagonist RU 486 (mifepristone) causes menstrual bleeding when given during the luteal phase of the menstrual cycle (1) and induces abortion in 64-85% of pregnant patients when administered before the 50. postmenstrual days (2, 3). These clinical actions are thought to reflect the antiprogestational effects of RU 486. Pathologic studies showed, that the effects of RU 486 on primate and human luteal phase endometrium include reduced stromal edema, increased venular diameter. Erythrocyte and leukocyte diapedesis, focal hemorrhage, degeneration of the stromal extracellular matrix, and eventual disruption of the superficial layer of the endometrium (4, 5). This antihormone acts at the receptor level and possibly also at the postreceptor level(s) (6). The most important mechanism of action is to compete with progesterone at the level of their respective binding site in the ligand binding domain of the progesterone receptors. The binding of RU 486 to the receptor leads to conformational changes in the DNA-binding site of the progesterone-receptor (7). As a consequnce of these changes, the interaction between the receptor and the progesterone-response elements in the promoter region of progesterone-responsive genes is altered (7). The menorrhagic and abortifacient properties of RU 486 are associated with the induction of endometrial hemorrhage. The physiological mechanisms by which human endometrium permits menstrual hemorrhage in the absence of pregnancy yet maintains hemostasis during endovascular trophoblast invasion (avoiding early abortion) has been investigated in our laboratory by evaluating endometrial expression of different proteins that play role in the process of hemostasis. Besides the endometrial haemostasis, we also examined the proteolytic processes leading extracellular matrix (ECM) degradation, which is also an integral part of menstruation. In this review we sought to summarize the biological mechanisms underlying the clinical effects of RU 486 on endometrial haemorrhage/haemostasis and on ECM degradation.
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PMID:Biological mechanisms underlying the clinical effects of mifepristone (RU 486) on the endometrium. 1174 18

Progesterone-induced decidualized human endometrial stromal cells form a hemostatic envelope that protects against hemorrhage during invasion of endometrial capillaries by implanting blastocyst-derived cytotrophoblasts (CTs). This hemostatic milieu reflects co-upregulated expression of tissue factor (TF), the primary initiator of hemostasis via thrombin generation and plasminogen activator inhibitor type 1, which inactivates tissue-type plasminogen activator, the primary fibrinolytic agent. During deep invasion of the decidua, CTs breach and remodel spiral arteries and arterioles to produce high-conductance vessels. Shallow invasion results in incomplete vascular transformation and an underperfused fetal - placental unit associated with preeclampsia and intrauterine growth restriction. Decidual hemorrhage and severe thrombophilias elicit aberrant thrombin generation from decidual cell-expressed TF. Such thrombin induces decidual cells to synthesize and secrete soluble fms-like tyrosine kinase-1 (sFlt-1), the matrix metalloproteinases MMP-1 and MMP-3, and the neutrophil chemoattractant interleukin-8. Excess sFlt-1 at the implantation site may inhibit CT invasion by altering the angiogenic factor balance. During abruptions, thrombin-enhanced MMP-1, MMP-3 by decidual cells and neutrophil-derived proteases degrade the decidual and fetal membrane extracellular matrix to promote preterm premature rupture of the membranes. In association with long-term progestin-only contraception, overexpression of decidual cell-derived thrombin promotes aberrant angiogenesis and vessel maintenance to contribute to abnormal uterine bleeding.
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PMID:The role of decidualization in regulating endometrial hemostasis during the menstrual cycle, gestation, and in pathological states. 1725 97

The purpose of this study was to clarify the precise effect of argatroban on the inhibition of cytokine secretion induced by thrombin on synovial cells. The efficiency of thrombin inactivation by thrombin inhibitors was evaluated in human synovial fluids (SFs). In SFs from 13 osteoarthritis (OA) and 11 rheumatoid arthritis (RA) patients, thrombin, Factor Xa (FXa), plasmin activity, IL-6, MMP-3, VEGF, and D-dimer concentrations were measured. Tissue factor (TF) activity or IL-6, MMP-3, and VEGF secretion of human synovial cells with or without thrombin and argatroban were measured. The efficiency of thrombin inactivation in SFs was compared for thrombin inhibitors: argatroban, antithrombin III (ATIII), or heparin cofactor II (HCII). In SFs, thrombin, FXa, plasmin, D-dimer, IL-6, and MMP-3 were significantly higher in RA than in OA. In synovial cell experiments, TNF-alpha and thrombin enhanced TF activity on the cell surface, and IL-6, MMP-3, and VEGF secretion were enhanced by thrombin. Increased TF activity, and IL-6, MMP-3, and VEGF secretion induced by thrombin were inhibited by argatroban. In SFs, argatroban inactivated thrombin more effectively than ATIII or HCII. Since thrombin plays an important role in the disease activity of OA and RA, it is a potential therapeutic molecular target. Argatroban was the most effective anticoagulant to inhibit thrombin activity in SF. Intra-articular injection is ideal administration because it can deliver high dose of argatroban without high risk of systematic complication.
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PMID:Argatroban more effectively inhibits the thrombin activity in synovial fluid than naturally occurring thrombin inhibitors. 2726 98

Structural changes in nucleus pulposus cells induce intervertebral disc (IVD) degeneration as a consequence of cytokine generation, biochemical products, and changes in the local environment. We have previously shown that inflammatory cytokines induce murine IVD (mIVD) angiogenesis and macrophage migration. Although the physiological roles of thrombin, a known proinflammatory factor, are documented, its relationship to IVD degeneration remains largely unexplored. Thrombin mediates cellular responses via the activation of protease-activated receptors such as PAR1 which has been studied in numerous cell types, but not extensively in IVD cells. This study was designed to investigate the endogenous expression of thrombin, tissue factor, and PAR1 in cultured coccygeal mIVDs. Thrombin exclusively induced MCP-1 via the MAPK-ERK and PI3K-AKT pathways. MCP-1 produced by mIVDs induced macrophage migration and thrombin treatment increased MMP-3 production to induce mIVD degeneration. These effects of thrombin on mIVDs were abrogated by a PAR1 inhibitor and suggest that thrombin may be a novel factor capable of stimulating cytokine activity implicated in the regulation several aspects of mIVDs. Mechanisms governing mIVDs, which are regulated by thrombin/PAR1 signaling, require elucidation if our understanding of IVD degenerative mechanisms is to advance.
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PMID:Effect of Thrombin-Induced MCP-1 and MMP-3 Production Via PAR1 Expression in Murine Intervertebral Discs. 3005 81