Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperlipidemia, especially hypercholesterolemia, may contribute to glomerulosclerosis as it does to atherosclerosis. Low density lipoprotein (LDL) stimulates the production of extracellular matrix by mesangial cells in culture as well as the proliferation of mesangial cells. This study was carried out to examine the effects of LDL on the type IV collagen (CIV) production by cultured rat mesangial cells (CRMC). Subconfluent CRMC monolayers which were grown in RPMI with 20% lipid-free fetal calf serum for 48 h were challenged with LDL (0, 50, 100, 150 and 200 micrograms/ml) for another 48 h. LDL was prepared from normal human plasma. Mesangial cell proliferation was examined by [3H]-thymidine uptake. Production of CIV was evaluated as the expression of CIV on the cell surface by flow-cytometric analysis. The collagen synthesis was measured by the [3H]-proline uptake. Total RNA was extracted from CRMC at 6 and 24 h of incubation with 150 micrograms/ml LDL, and Northern blotting and hybridization was performed with cDNAs for alpha 1-CIV, for 72-kD collagenase and for tissue inhibitor of metalloproteinase (TIMP)-2. The amount of total mRNA was corrected with beta-actin mRNA. Mesangial cell proliferation increased in all concentrations studied and had a peak value of 221% with 150 micrograms/ml of LDL. Expression of CIV increased by 30-60% in 100-200 micrograms/ml of LDL. Collagen synthesis also increased by 50-70% in 150-200 micrograms/ml of LDL. The mRNA ratio (procollagen alpha 1(IV)/beta-actin) increased to 133% at 24 h. The mRNA ratio (TIMP-2/beta-actin) increased to 137% at 24 h. mRNA ratios at 6 h showed no change.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of low density lipoprotein on type IV collagen production by cultured rat mesangial cells. 793 24

We review the importance of extracellular matrix remodelling to the processes of vascular smooth muscle cell migration and proliferation that contribute to morphogenesis of the atherosclerotic plaque. In particular, the role of the matrix degrading metalloproteinase (MMP) family is discussed. This family of neutral, ZN(2+)-requiring enzymes are capable, in principle, of degrading all matrix proteins. Their activity is tightly controlled, however, at the level of synthesis of the inactive zymogens, activation by limited proteolysis and binding to endogenous inhibitor proteins (TIMPs). Direct evidence is presented for the involvement of MMPs in proliferation and outgrowth of vascular smooth muscle cells from explants of rabbit aorta in vitro. This was obtained using two structurally-unrelated inhibitors of MMPs, Ro 31-4724 and Ro 31-7467, both of which inhibited proliferation of cells in a concentration-dependent manner, Ro 31-4724 also inhibited outgrowth. Rabbit aortic smooth muscle cells were further shown to release MMPs, namely a 95 and a 72 kDa gelatinases that were inhibited by Ro 31-4724 and Ro 31-7467. The evidence suggests that degradation of basement membrane by gelatinase is required for proliferation and outgrowth of these cells. The implications of these findings for the pathogenesis and treatment of atherosclerosis are also discussed.
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PMID:Extracellular matrix degrading metalloproteinases in the pathogenesis of arteriosclerosis. 794 77

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

Endothelin (ET)-1 is an endothelium-derived vasoconstrictor and mitogen peptide generated from an intermediate form (big ET-1) by endothelin-converting enzyme(s) (ECE). In this study, we partially characterized ECE activity in human serum lipoprotein fraction. By gel filtration chromatography, lipoprotein ECE activities consisted of three major components: the first and the second peak eluted in the positions of very low density lipoprotein (VLDL) and low density lipoprotein (LDL), respectively, while the third peak eluted earlier than that of high density lipoprotein (HDL), whose apparent molecular weight (550 kDa) was similar to that of apolipoprotein B (apo B). Both VLDL/LDL-associated and free ECE fractions were similarly inhibited by metalloproteinase and serine proteinase inhibitors. Free ECE fraction was precipitable with dextran sulphate and manganese ion in the same manner as lipoprotein ECE. Apo B purified by high performance liquid chromatography had the same ECE activity as lipoprotein ECE, whose activity was removed after immunoprecipitation with polyclonal anti-apo B antibody. Our data suggest that ECE activity in human serum lipoproteins may be associated with an apo B-like component, although it needs to be characterized completely.
Atherosclerosis 1994 Aug
PMID:Partial characterization of endothelin-converting enzyme activity in human serum lipoproteins. 798 Jul 17

MMP-2, a secreted 72-kd metalloproteinase that specifically degrades type IV collagen as well as denatured collagens, has been implicated in smooth muscle cell migration. To evaluate the possible contribution of this enzyme to the formation and progression of the atherosclerotic lesion, the expression of MMP-2 was studied in human aortic tissue. MMP-2 was visualized in frozen sections of the aortic wall by an immunofluorescent technique with a polyclonal antibody. Expression of MMP-2 in the aortic extracts was also studied by zymography and Western blotting. Our results reveal that a greater amount of MMP-2 is present in fatty streaks and atherosclerotic plaques as compared with normal regions of the aorta. Immunoblotting analysis showed that MMP-2 was expressed in atherosclerotic plaque > fatty streak > normal aortic wall in a ratio of approximately 4:2:1. Zymograms show that both forms (activated and latent) of MMP-2 increased in the atherosclerotic plaques. The presence of macrophages, detected by an immunohistochemical technique in some areas of higher MMP-2 expression suggests that these cells are a possible source of MMP-2. We conclude that MMP-2 collagenase may have a role in the formation and progression of the atherosclerotic lesion and may be involved in clinical complications of atherosclerosis, such as fissure and rupture, leading to thrombosis.
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PMID:Increased expression of 72-kd type IV collagenase (MMP-2) in human aortic atherosclerotic lesions. 854 99

Remodelling of the extracellular matrix resulting from increased secretion of metalloproteinase enzymes (MMPs) is implicated in many pathological conditions, including rheumatoid arthritis, restenosis following balloon angioplasty, atherosclerosis and cancer cell invasion and metastasis. Clear definition of the normal and pathological function of individual MMPs will benefit from approaches that use gene transfer to produce increases in MMP levels that mimic those observed in pathological conditions. Similarly, gene transfer methods leading to controlled increases in levels of the tissue inhibitor of metalloproteinases (TIMPs) will help to define the function of MMPs both in vitro and in vivo. Gene transfer of TIMPs may also have therapeutic potential in pathological conditions where inhibition of MMP activity may be beneficial. We have used the adenovirus serotype 5 vector system to generate replication-deficient recombinant adenoviruses capable of expressing the MMP-9, TIMP-1 or -2 genes. High level expression is driven by the cytomegalovirus major immediate early promoter (CMV IEP). Efficient and selective over-production of each recombinant protein was shown by immunofluorescence in either rabbit smooth muscle cells (SMC) or human MCF-7 adenocarcinoma cells. High level secretion directly dependent on the multiplicity of infection (MOI) was observed for each functional transgene by gelatin zymography. Using a quantitative ELISA assay, levels of recombinant TIMP-1 were detected when SMC were infected with as low as three plaque forming units (pfu) of virus per cell in vitro. A linear increase in TIMP-1 secretion was observed up to 1000 pfu/cell of virus (0.75 ng/10(4) cells/24 h at 3 pfu/cell to 1243 ng/10(4) cells/24h at 1000 pfu/cell). Similar levels of secretion of MMP-9 and TIMP-2 were observed by Western blot analysis using the same MOI of adenovirus. Thus, recombinant adenoviruses are an efficient and flexible system for high level expression of MMPs and TIMPs and will be useful tools in the study of matrix remodelling in vivo and in vitro.
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PMID:Development of recombinant adenoviruses that drive high level expression of the human metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 and -2 genes: characterization of their infection into rabbit smooth muscle cells and human MCF-7 adenocarcinoma cells. 904 77

Blood platelets limit blood loss at sites of vascular injury by forming a mechanical plug. They are also involved in thrombosis, atherosclerosis, inflammation and metastasis. Platelet activation is essential for these physiological and pathological reactions and depends upon their adhesion to the vessel wall and attachment to each other in the aggregation process. The two known pathways of aggregation are mediated by the release of endoperoxides/thromboxane A2 and ADP which amplify platelet aggregation. Here we report the identification of a new pathway of aggregation which is mediated by the release of a metalloproteinase enzyme, gelatinase A.
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PMID:Release of gelatinase A during platelet activation mediates aggregation. 912 86

Immunocompetent cells infiltrate atherosclerotic plaques of all stages. Plaque-infiltrating T-cells recognize oxidized LDL and heat shock proteins and this elicits antibody responses that have been proposed as markers of disease activity. Cytokines secreted by activated T-cells may control macrophage activation, scavenger receptor expression and metalloproteinase secretion. Furthermore, cytokines secreted by T-cells and macrophages modulate smooth muscle proliferation, nitric oxide production and apoptosis, and induce endothelial activation. However, both positive and negative signals, as well as feedback loops, may be induced because of the complexity of the immune system. The possibility that some of these signals may be protective against atherosclerosis is currently under investigation in several laboratories. Recent studies in experimental animals show that immunomodulation affects the development of plaques and that immunization with oxidized LDL can inhibit lesion formation. This review provides a brief overview of cellular immunology and an analysis of its potential role in atherogenesis.
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PMID:Cell-mediated immunity in atherosclerosis. 933 54

Monocyte-endothelial cell interactions play an important role in the early stages of atherosclerosis, and it is hypothesized that regulation of metalloproteinase production by these interactions contributes to this pathological process. The effects of monocytic cell-endothelial cell interactions on monocytic metalloproteinase production were investigated using an in vitro system, focusing on the role of endothelial cell secretions and physical contact as effectors in the regulation of monocytic metalloproteinase expression. Human umbilical vein endothelial cells (HUVECs) and the human monocytic cell line THP-1 were used, and changes in the levels of THP-1 metalloproteinase secretion and mRNA were measured. When THP-1 cells were incubated for 18 hours with HUVEC conditioned medium (CM), a four- to eightfold induction of the metalloproteinase MMP-9 was observed at both the mRNA and protein levels; however, levels of another metalloproteinase, MMP-2, were unaffected. The induction of MMP-9 by HUVEC CM was confirmed using freshly isolated human monocytes. A sevenfold increase in MMP-9 levels was observed with apically collected HUVEC CM but not with basally collected CM. THP-1 cells incubated with paraformaldehyde-fixed HUVECs and isolated HUVEC plasma membranes showed an eightfold increase in MMP-9 levels, and measurements of MMP-9 activity found in THP-1 conditioned medium due to either HUVEC contact or HUVEC CM showed a threefold increase. The molecular weight of the endothelial secreted effector molecule(s) was determined to be 30 +/- 6 kd. The data show that endothelial cells through the release of soluble factors and through direct contact with monocytic cells regulate monocytic metalloproteinase production, which has implications for the atherogenic process.
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PMID:Interactions of monocytic cells with human endothelial cells stimulate monocytic metalloproteinase production. 942 37

Neointimal formation involving smooth muscle cell (SMC) migration and proliferation is a common feature of atherosclerosis, restenosis after angioplasty, and vein graft intimal thickening. Extracellular matrix remodeling by metalloproteinase (MMP) enzymes is an essential component of neointimal formation and therefore MMPs are a potential target for localized gene therapy. To evaluate this concept using human tissue, we used the highly reproducible organ culture model of neointimal formation in human saphenous vein to investigate the effect of adenovirus-mediated gene transfer of tissue inhibitor of metalloproteinase 1 (TIMP-1) and the bacterial LacZ gene (RAd35) as a control. Incubating veins with 100 microl of RAd35 (1.2 x 10(10) pfu/ml) led to expression of LacZ in 39 +/- 7% of surface cells but had no effect on SMC proliferation, migration, or neointimal formation. Similar infection with RAdTIMP-1 increased explanation of TIMP-1 in surface cells and significantly inhibited neointimal formation and SMC migration after 14 days by 54% and 78%, respectively (n = 6, p < 0.05 Student's paired t test). No effect on SMC proliferation or deleterious effect on cell viability was observed. A specific MMP inhibitory effect was detected using in situ zymography. These data confirm the importance of MMPs in neointimal formation and highlight the potential for application of TIMP gene therapy.
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PMID:Adenovirus-mediated gene transfer of the human TIMP-1 gene inhibits smooth muscle cell migration and neointimal formation in human saphenous vein. 958 9


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