Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We established two cell lines of human smooth muscle cells (SMC) by transfection of cells from the aortic intima and aortic media with origin-minus simian virus 40 (ori-minus SV40) DNA. Ori-minus SV40 DNA very efficiently immortalized human smooth muscle cells in culture. Proteins that these cell lines produced included type I, III, IV, and V collagens, fibronectin, and human matrix metalloproteinases (MMP)-1 (tissue collagenase), -2 ("type IV collagenase"), and -3 (stromelysin). The protein production in these cell lines generally mimicked that of normal SMC, but the immortalization stimulated the cell line of medial SMC to produce excessive MMP-2 and to secrete MMP-9 (92-kDa gelatinase). However, since these cell lines did not show a fully malignant phenotype, we concluded that, in addition to the degradation of extracellular matrix macromolecules, including basement membrane components by MMP-2, -3, and/or -9, some additional factors must be involved for the malignancy of fully transformed cells and that these immortalized human aortic SMC, which share many characteristics with normal SMC, will prove useful to study the role(s) of metalloproteinases in atherosclerosis.
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PMID:Immortalization of human aortic smooth muscle cells with origin-minus simian virus 40 DNA. 133 71

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cell-specific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not. Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. In vitro, lipid-laden aortic macrophages, but not alveolar macrophages, synthesized de novo and released immunoprecipitable stromelysin and collagenase, with or without stimulation by phorbol ester or bacterial lipopolysaccharide. These stimuli caused foam cells to release additional gelatinolytic activity that migrated faster than a purified preparation of 92-kDa gelatinase in substrate-containing polyacrylamide gels, indicating activation of the 92-kDa gelatinase or induction of the 72-kDa gelatinase. Our results show that lipid-laden macrophages elaborate MMPs capable of degrading the major constituents of vascular extracellular matrix even without further stimulation. Therefore, these cells may contribute to remodeling of the extracellular matrix during atherogenesis and to the disruption of plaques often responsible for acute clinical manifestations of atherosclerosis.
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PMID:Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. 783 Dec 99

Degradation of elastic fibers in the arterial walls is an important step in the development of atherosclerosis. To identify the enzyme(s) responsible for the elastinolysis, we have designed an ex vivo model of aortic explants cultured with or without THP-1 cells (human monocyte/macrophage-like cells). After culturing with THP-1 cells for 5 days elastic fibers of the aortic explants were fragmented and lost. With insoluble [3H] elastin as a substrate, elastin-degrading activity could be detected in the culture medium. Zymography in sodium dodecyl sulfate-polyacrylamide gel electrophoresis containing alpha-elastin showed the presence of elastinolytic activity with 92 kd in the medium from the aortic tissue with THP-1 cell cultures, whereas the medium from the aortic tissue without THP-1 cells contained negligible elastinolytic activity. The activity was inhibited by ethylenediamine tetraacetic acid but not by phenylmethane sulfonyl fluoride, N-ethylmaleimide, or pepstatin A, indicating that the enzyme belongs to a class of metalloproteinases. In addition, destruction of the elastic fibers of the aortic explants cultured with THP-1 cells was completely inhibited only by metalloproteinase inhibitors. Immunoblot analyses demonstrated that the proteinase responsible for the elastinolytic activity is matrix metalloproteinase-9 (92-kd gelatinase/type IV collagenase = gelatinase B). Using immunocytochemistry, the metalloproteinase was localized in the THP-1 cells but not in the medial smooth muscle cells. These results suggest that matrix metalloproteinase-9 produced by THP-1 cells is of importance to degradation of elastic fibers in the aortic explants. The role of macrophages in the atherosclerosis is discussed with reference to elastinolysis of the arterial walls.
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PMID:Matrix metalloproteinase-9 (92-kd gelatinase/type IV collagenase equals gelatinase B) can degrade arterial elastin. 797 51

The migration and proliferation of vascular smooth muscle cells (SMCs) during neointima formation in atherosclerosis and angioplasty restenosis is mediated by certain growth factors and cytokines, one action of which may be to promote basement-membrane degradation. To test this hypothesis further, the effects of such growth factors and cytokines on the synthesis of two basement-membrane-degrading metalloproteinases, namely the 72 kDa gelatinase (MMP-2, gelatinase A) and the 95 kDa gelatinase (MMP-9, gelatinase B) and three tissue inhibitors of metalloproteinases (TIMPs) was studied in primary cultured rabbit aortic SMCs. Expression of the 95 kDa gelatinase was increased by phorbol myristate acetate, foetal calf serum, thrombin and interleukin-1alpha (IL-1alpha); platelet-derived growth factor (PDGF) BB alone had no effect but acted synergistically with IL-1alpha. A selective protein kinase C inhibitor, Ro 31-8220, abolished induction of the 95 kDa gelatinase. In contrast, none of the agents tested modulated the synthesis of the 72 kDa gelatinase. We conclude that maximal up-regulation of 95 kDa gelatinase expression requires the concerted action of growth factors and inflammatory cytokines mediated, in part, by a protein kinase C-dependent pathway. TIMP-1 and TIMP-2 were highly expressed, and their synthesis was not affected by growth factors or cytokines. Expression of TIMP-3 mRNAs was, however, increased by PDGF and transforming growth factor beta, especially in combination. Divergent regulation of gelatinase and TIMP expression implies that either net synthesis or net degradation of basement membrane can be mediated by appropriate combinations of growth factors and cytokines.
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PMID:Divergent regulation by growth factors and cytokines of 95 kDa and 72 kDa gelatinases and tissue inhibitors or metalloproteinases-1, -2, and -3 in rabbit aortic smooth muscle cells. 867 Jan 28

Basement membrane degrading metalloproteinases (gelatinases) have been implicated in the regulation of vascular smooth muscle cell migration and proliferation in culture and during neointima formation in vivo. We compared the expression and activation of gelatinases A and B in explants derived from the arch, mid and distal portions of thoracic aortas of normal rabbits and those given a 1% cholesterol-containing diet for 8 weeks. Neointimal/medial ratio was less than 0.01 in normal rabbits but was significantly increased by cholesterol feeding in the arch (1.08 +/- 0.26), mid (0.75 +/- 0.28) and distal (0.32 +/- 0.12) portions of the aorta (mean +/- S.E.M., n = 6), and to a significantly (P < 0.05) greater extent in the arch and mid than distal portions. Secretion of gelatinase B measured by densitometric scanning of zymograms was undetectable from normal aortas, but was significantly increased by cholesterol feeding in the arch (0.16 +/- 0.06), mid (0.26 +/- 0.08) and distal (0.11 +/- 0.05) portions (optical density units, n = 6, each P < 0.05 versus normal diet). The increase in gelatinase B expression was localised by in situ hybridisation to neointimal vascular smooth muscle cells, macrophages and endothelial cells. Secretion of pro-gelatinase A was detected from normal aortas; it was increased by cholesterol feeding from the arch (4.0 versus 2.8, P < 0.05) and mid (3.6 versus 2.8, P < 0.05) but not distal portions of the aorta (1.8 versus 1.2, n.s.). Similar results were obtained for active gelatinase A secretion from the arch (0.50 versus 0.28, P < 0.05) and mid (0.47 versus 0.23, P < 0.05) but not distal portions (0.19 versus 0.20, n.s.). Increases in pro- and active gelatinase A secretion therefore paralleled the severity of atheroma formation. The results imply that increased basement membrane turnover mediated by gelatinases occurs during cholesterol induced atherosclerosis formation.
Atherosclerosis 1997 Apr
PMID:Increased secretion of gelatinases A and B from the aortas of cholesterol fed rabbits: relationship to lesion severity. 912 49

PD 166285, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido[2,3-d]pyrimidines, was synthesized as the most potent and soluble analog of a series of small molecules originally identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 166285 was found to inhibit Src nonreceptor tyrosine kinase, fibroblast growth factor receptor-1, epidermal growth factor receptor and platelet-derived growth factor receptor beta subunit (PDGFR-beta), tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 8.4 +/- 2.3 nM (n = 6), 39.3 +/- 2.8 nM (n = 16), 87.5 +/- 13.7 nM (n = 6) and 98.3 +/- 7.9 nM (n = 16), respectively. PD 166285 also demonstrated inhibitory activity against mitogen-activated protein kinase (IC50 = 5 microM) and protein kinase C (IC50 = 22.7 microM). PD 166285 was further characterized as an ATP competitive inhibitor of Src nonreceptor tyrosine kinase, PDGFR-beta, fibroblast growth factor receptor-1 and epidermal growth factor receptor tyrosine kinases. In addition, PD 166285 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular smooth muscle cells (VSMCs) and A431 cells, respectively, and basic fibroblast growth factor-mediated tyrosine phosphorylation in Sf9 cells, with IC50 values of 6.5 nM, 1.6 microM and 97.3 nM, respectively, further establishing a tyrosine kinase mechanism of inhibition. The inhibition of PDGF receptor autophosphorylation in VSMCs by PD 166285 was long lasting and persisted for 4 days after a single 1-hr exposure followed by extensive washing. The PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 166285 in VSMCs. The effects of PD 166285 were also demonstrated in functional assays of cell attachment, migration and proliferation, in which vascular cell adhesion to vitronectin, PDGF-directed chemotaxis and serum-stimulated cell growth were all potently inhibited with IC50 values of 80 yo 120 nM. Finally, PD 166285 uniquely demonstrated potent inhibition of phorbol ester-induced production of 92-kDa gelatinase A (MMP-9) in VSMC without affecting 72-kDa gelatinase B (MMP-2) as measured by gelatin zymography. These results highlight the biological characteristics of PD 166285 as a broadly active protein tyrosine kinase capable of potently inhibiting a number of kinase mediated cellular functions, including cell attachment, movement and replication. The potential therapeutic utility of this broadly acting inhibitor as an antiproliferative and antimigratory agent could extend to such diseases as cancer, atherosclerosis and restenosis, in which redundancies in protein kinase signaling pathways are known to exist.
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PMID:In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. 940 19

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen. PPAR-gamma has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates. Naturally occurring compounds such as fatty acids and the prostaglandin D2 metabolite 15-deoxy-delta prostaglandin J2 (15d-PGJ2) bind to PPAR-gamma and stimulate transcription of target genes. Prostaglandin D2 metabolites have not yet been identified in adipose tissue, but are major products of arachidonic-acid metabolism in macrophages, raising the possibility that they might serve as endogenous PPAR-gamma ligands in this cell type. Here we show that PPAR-gamma is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPAR-gamma ligands. PPAR-gamma inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-kappaB. These observations suggest that PPAR-gamma and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR-gamma ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects.
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PMID:The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. 942 8

1. Changes in the environmental oxygen tension to which cells are exposed in vivo result in physiological and sometimes pathological consequences that are associated with differential expression of specific genes. 2. Low oxygen tension (hypoxia) affects endothelial cellular physiology in vivo and in vitro in a number of ways, including the transcriptionally regulated expression of vasoactive substances and matrix proteins involved in modulating vascular tone or remodelling the vasculature and surrounding tissue. 3. Hypoxia results in the transcriptional induction of genes encoding vasoconstrictors and smooth muscle mitogens (PDGF-B, endothelin-1, VEGF, thrombospondin-1) and genes encoding matrix or remodelling molecules (collagenase IV (MMP-9), thrombospondin-1) and reciprocal transcriptional inhibition of vasodilatory or anti-mitogenic effectors (eNOS). 4. Oxygen appears to signal through a novel haem-containing sensor and signals initiated by this sensor alter the levels and DNA-binding activity of transcription factors such as activating protein (AP)-1, nuclear factor-kappa B and hypoxia-inducible transcription factor-1. 5. The genes encoding vasoactive factors regulated by oxygen tension are themselves also regulated by the vasoactive agent nitric oxide (NO). 6. Nitric oxide and oxygen transduce similar signals (i.e. their absence results in identical patterns of gene expression in endothelial cells and other cell types). 7. Thus, NO can feedback on and modulate signals induced by hypoxia and vice versa. For example, NO, which can act directly on smooth muscle cells as a vasodilator, can also facilitate vasodilation indirectly by reversing the production of vasoconstrictors induced by hypoxia. 8. Short-term exposure of endothelial cells to low oxygen tension results in the elaboration of predominantly vasoconstricting effectors, while longer-term and more severe hypoxic exposure generates factors that can induce smooth muscle proliferation and remodelling. 9. Thus, the endothelial cell response to hypoxic stress can result in two different consequences in the surrounding tissues, depending on the duration of the exposure: short-term exposure causes physiological and reversible modulation of vascular tone and blood flow; chronic hypoxic stress results in irreversible remodelling of the vasculature and surrounding tissues, with smooth muscle proliferation and fibrosis. 10. This dichotomy of responses to hypoxia may explain, in part, both the acute and chronic pathophysiological sequelae of diseases characterized by regional hypoxia, including atherosclerosis, pulmonary hypertension, sickle cell disease and systemic sclerosis (scleroderma).
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PMID:Endothelial cell responses to hypoxic stress. 1090 94

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that directly control numerous genes of lipid metabolism by binding to response elements in the promoter. It has recently been proposed that PPARgamma may also regulate genes for proinflammatory proteins, not through PPRE binding but by interaction with transcription factors AP-1, STAT, and NF-kappaB. Recent studies with cultured human monocytes, however, have failed to observe an inhibitory effect of PPARgamma agonists on induced expression of TNFalpha and IL-6, genes known to be controlled by AP-1, STAT, and NF-kappaB. In a similar fashion, we show here that PPARalpha (fenofibrate) or PPARgamma (rosiglitazone) agonists failed to modulate LPS-induced secretion of IL-8 in THP-1 cells. When we made parallel observations on another gene, matrix metalloproteinase 9 (MMP-9), we were surprised to find profound downregulation of LPS-induced secretion by both PPARalpha or PPARgamma agonists. These findings suggest that PPAR may regulate only a subset of the proinflammatory genes controlled by AP-1, STAT, and NF-kappaB. Effects of PPARs on MMP-9 may account for the beneficial effect of PPAR agonists in animal models of atherosclerosis.
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PMID:Activation of PPARalpha or gamma reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells. 1062 22

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPARgamma is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPARgamma-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor-deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-alpha and gelatinase B, indicating both systemic and local actions of PPARgamma. These findings suggest that PPARgamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPARgamma ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.
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PMID:Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. 1097 14


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