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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A chondroitin sulfate-dermatan sulfate proteoglycan was isolated from bovine aorta intima by extraction of the tissue with 4 M guanidine hydrochloride. The proteoglycan was purified by CsCl isopycnic centrifugation followed by gel filtration and ion exchange chromatography. A monoclonal antibody C8F4 was developed to this core protein. The characteristics and specificity of the antibody were studied by an enzyme-linked immunosorbent assay (ELISA) using an alkaline phosphatase conjugated antibody (goat anti-mouse IgG). The antibody binding to the core protein was found specific and optimal at pH 7.0. The antibody recognizes either intact chondroitin sulfate-dermatan sulfate proteoglycan monomer, chondroitinase ABC digested monomer or chemically deglycosylated proteoglycan. Free chondroitin sulfates, keratan sulfate and hyaluronic acid did not compete for the antigenic sites in ELISA. Limited hydrolysis of the core protein by trypsin resulted in three peptides and only the peptide with a molecular weight M(r) = 40,000 was found capable of binding to hyaluronic acid. The antibody C8F4 recognized this hyaluronic acid binding peptide but did not recognize the other two peptides suggesting that the epitope(s) for this antibody is in the hyaluronic acid-binding region of the core protein. The antibody recognized the core proteins from bovine nasal cartilage proteoglycan and human aorta proteoglycan but did not recognize bovine aorta link protein, bovine serum albumin, human serum albumin, human transferrin, collagen Type I and fibronectin. The antibody was found useful to localize proteoglycans in atherosclerotic lesions in human aorta by immunohistochemical techniques.
Atherosclerosis 1993 Jan 25
PMID:A monoclonal antibody that recognizes hyaluronic acid binding region of aorta proteoglycans. 768 Dec 90

It has previously been shown that lipoprotein lipase can mediate uptake of remnant lipoprotein particles via binding to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP). Binding of lipoprotein lipase, and of triglyceride-rich lipoproteins associated with the lipase, to LRP depends on an intact carboxyl-terminal folding domain of the lipase (Nykjaer, A., Bengtsson-Olivecrona, G., Lookene, A., Moestrup, S. K., Petersen, C. M., Weber, W., Beisiegel, W., and Gliemann, J. (1993) J. Biol. Chem. 268, 15048-15055). Here we show that the site for binding to the receptor is within residues 380-425 of the bovine and residues 378-423 of the human lipoprotein lipase. We demonstrate that a carboxyl-terminal fragment of human lipoprotein lipase (residues 378-448), expressed as fusion protein in Escherichia coli, binds to purified and cellular LRP but not to lipoproteins. Binding of the fragment to purified LRP was blocked by heparin. In addition, the fragment inhibited the binding of lipase and the lipase-mediated binding of lipoproteins to the purified receptor. The fragment exhibited reduced binding to proteoglycan-deficient cells. Moreover, the fragment inhibited the uptake of lipoproteins in cells mediated by the lipase via binding to heparan sulfate proteoglycans and LRP. We conclude that the fragment contains the site for binding to LRP and a candidate site for interaction with heparan sulfate proteoglycans, whereas binding to lipoproteins is inefficient. The fragment can therefore inhibit the lipase-mediated lipoprotein uptake, a process that may promote the development of atherosclerosis when occurring in cells of the arterial wall.
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PMID:A carboxyl-terminal fragment of lipoprotein lipase binds to the low density lipoprotein receptor-related protein and inhibits lipase-mediated uptake of lipoprotein in cells. 798 48

The complex polymeric structure of heparan sulphate contains intra-chain sequences of sulphated sugar residues that define active sites for the binding and activation of growth factors. The molecular mechanisms of recognition and activation are slowly being revealed at least in the case of the interaction of heparan sulphate with basic fibroblast growth factor. Current data indicate that relatively long but specific binding sequences in heparan sulphate may induce a conformational change in basic fibroblast growth factor exposing a site on the protein that is recognised by signal transducing receptors. Heparan sulphate may also subserve functions of dimerisation of basic fibroblast growth factor and facilitation of receptor transfer by a secondary interaction with the receptor itself. Various models for heparan sulphate mediated induction of mitogenesis by basic fibroblast growth factor have been proposed and there are suggestions that the core protein of plasma membrane heparan sulphate-proteoglycans may participate in the cell signalling process. The vital importance of heparan sulphate in controlling growth factor activities has opened up a new chapter in proteoglycan research and has brought proteoglycans into the mainstream of cell biology. Further investigation of their mode of action is likely to reveal new information on the control of cell growth and development in both embryonic and adult tissues and may suggest novel methods of controlling diseases such as cancer, atherosclerosis or fibrosis that are driven by abnormal expression of growth factors or their receptors.
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PMID:Heparan sulphates as membrane receptors for the fibroblast growth factors. 803 64

Lipoprotein-proteoglycan (LP-PG) complexes are taken up more avidly by macrophages and smooth muscle cells (SMCs) than native lipoproteins (LPs). The enhanced uptake may contribute to lipid accumulation and foam cell formation during atherogenesis. Endothelial injury is known to alter proteoglycan (PG) synthesis and distribution in the neointima developed in response to injury. The present study examines the uptake and degradation of LP-PG complexes, derived from PG of injured aortas by arterial SMCs. Rabbit apo-B lipoprotein (LP), including VLDL, IDL and LDL was isolated by ultracentrifugation and coupled with PG extracted from normal aortas (NPG) or with PG from injured aortas (IPG). Rabbit aortic SMCs were cultured from intima-media explants, incubated with 125I-LP, 125I-LP-NPG or 125I-LP-IPG for 20 h at 37 degrees C. LP binding, internalization and degradation were markedly increased (P < 0.001) for LP-NPG and LP-IPG over native LP. Competition experiments indicated that more than 50% of the LP-PG complexes were taken up by the apo-B/E receptor pathway. Phagocytosis was the second important route of uptake of these complexes, whereas the scavenger receptor played a minor part in the uptake and degradation of LP-PG complexes. Data from this study indicate that LP-PG complexes accelerate LP uptake and degradation by SMC more than native LP. Therefore, these complexes may contribute to lipid accumulation by SMC, thus generating foam cells. Furthermore, LP-PG complexes prepared from PG of injured aortas are more effective in lipid accumulation than LP-PG complexes from PG of normal aortas.
Atherosclerosis 1994 Jan
PMID:Lipoprotein-proteoglycan complexes from injured rabbit aortas accelerate lipoprotein uptake by arterial smooth muscle cells. 815 89

Proteoglycans are important constituents of blood vessels and accumulate in various forms of vascular disease. Little is known concerning the proteoglycan composition of restenotic lesions formed after angioplasty and whether the proteoglycan composition of these lesions differs from that of primary atherosclerosis. Accordingly, we sought to characterize the distribution of two proteoglycans, biglycan and decorin, in primary atherosclerotic and restenotic lesions of human coronary arteries. Restenosis (n = 37) and primary (n = 11) lesions obtained from 48 patients by directional atherectomy of human coronary arteries were stained with antibodies against biglycan and decorin. To further characterize the extracellular matrix of restenotic tissues, we studied the co-distribution of these proteoglycans with collagen types I, III, and IV. The loose fibroproliferative tissue seen predominantly in restenosis lesions consistently stained positively for biglycan in patterns of deposition ranging from disseminated to homogeneous. The density and intensity of biglycan staining was correlated with the density of collagen type I and III fiber networks, both of which were observed to interweave among the loose fibroproliferative tissue. The compact connective tissue of primary atherosclerotic plaque was characterized by strong biglycan staining which co-localized with intense collagen type I and III staining. Only basement membrane-like structures rich in collagen type IV demonstrated negative biglycan staining. In contrast, loose fibroproliferative tissue exhibited no significant staining for decorin. Strong immunostaining for decorin, however, was found in primary atherosclerotic plaque. There are thus regional differences in the distribution of extracellular matrix proteoglycans of restenotic and primary human atherosclerotic lesions; these observations suggest that differences established for the biological roles of biglycan and decorin in other organ systems may extend as well to pathologically altered human coronary arteries.
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PMID:Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries. 817 45

The arterial wall responds to thrombosis or mechanical injury through the induction of specific gene products that increase cellular proliferation and connective tissue formation. These changes result in intimal hyperplasia that is observed in restenosis and the early phases of atherosclerosis. Transforming growth factor beta 1 (TGF-beta 1) is a secreted multi-functional protein that plays an important role in embryonal development and in repair following tissue injury. However, the function of TGF-beta 1 in vascular cell growth in vivo has not been defined. In this report, we have evaluated the role of TGF-beta 1 in the pathophysiology of intimal and medial hyperplasia by gene transfer of an expression plasmid encoding active TGF-beta 1 into porcine arteries. Expression of TGF-beta 1 in normal arteries resulted in substantial extracellular matrix production accompanied by intimal and medial hyperplasia. Increased procollagen, collagen, and proteoglycan synthesis in the neointima was demonstrated by immunohistochemistry relative to control transfected arteries. Expression of TGF-beta 1 induced a distinctly different program of gene expression and biologic response from the platelet-derived growth factor B (PDGF B) gene: procollagen synthesis induced by TGF-beta 1 was greater, and cellular proliferation was less prominent. These findings show that TGF-beta 1 differentially modulates extracellular matrix production and cellular proliferation in the arterial wall in vivo and could play a reparative role in the response to arterial injury.
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PMID:Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia. 824 68

Certain fatty acids induce changes in endothelial barrier function which may be mediated by alterations in normal proteoglycan synthesis/metabolism. To test this hypothesis, pulmonary artery derived endothelial cells were treated with media supplemented with linoleic acid (18:2), and/or a known proteoglycan synthesis inhibitor, beta-D-xyloside. Independent exposure to 1 mM beta-D-xyloside or 90 microM 18:2 increased albumin transfer, i.e., decreased barrier function, when compared with control cultures. 18:2 and beta-D-xyloside increased albumin transfer additively, suggesting that the mechanisms by which 18:2 and beta-D-xyloside alter the proteoglycan metabolism are different. Compared with the control group, treatment with 18:2 inhibited proteoglycan synthesis, decreased anionic properties of heparan sulfate proteoglycans in the cell monolayers and caused the release of a unique chondroitin sulfate proteoglycan into the culture media. Treatment with beta-D-xyloside caused an increased incorporation of radioactive sulfate into glycosaminoglycans but inhibited proteoglycan synthesis. These results suggest that the fatty acid- and beta-D-xyloside-induced impairment in endothelial barrier function may involve changes in the synthesis, release and physicochemical properties of proteoglycans.
Atherosclerosis 1993 Nov
PMID:Proteoglycans and endothelial barrier function: effect of linoleic acid exposure to porcine pulmonary artery endothelial cells. 829 2

Contact between low density lipoproteins (LDL) and exocytosed mast cell granules, the "granule remnants," leads to binding of LDL to the granule remnants via ionic interactions between the apolipoprotein B-100 (apoB-100) component of LDL and the heparin proteoglycan component of the granule remnants. Upon incubation at 37 degrees C, the heparin proteoglycan-bound apoB-100 is progressively proteolyzed by remnant chymase and carboxypeptidase A, which are also bound to the heparin proteoglycans. Thereupon, the LDL particles fuse, and their binding to the granule remnants strengthens, as defined by the decreased ability of NaCl to release LDL from the remnants. We now have examined separately the effects of proteolysis and fusion on LDL binding. Proteolysis without fusion was induced by lowering the incubation temperature to 15 degrees C, and proteolysis-independent fusion was induced by treating granule remnant-bound LDL with sphingomyelinase in the presence of protease inhibitors. It was found that degradation of the heparin proteoglycan-bound apoB-100, even without accompanying particle fusion, increased the strength of LDL binding to the granule remnants, suggesting exposure of buried heparin binding regions of apoB-100. When such proteolyzed LDL particles were allowed to fuse, the strength of their binding to the granule remnants increased still further, probably because of an increase in the number of apoB-100 fragments in the enlarged particles. Proteolysis-independent fusion, induced by sphingomyelinase treatment of granule remnant-bound LDL, also increased the strength of binding. The results show that proteolytic degradation and fusion, the two modifications of granule remnant-bound LDL subsequent to action by chymase and carboxypeptidase A of the granule remnants, represent two separate mechanisms by which LDL particles become tightly bound to the heparin proteoglycans of exocytosed mast cell granules. Since the formation of an atheroma, the hallmark of atherosclerosis, is characterized by accumulation in the proteoglycan matrix of the arterial intima of extracellular lipid droplets resembling the fused LDL particles on the granule remnant surfaces, the modifications of LDL described in this study may provide a clue to the actual processes by which the lipid droplets are anchored to the arterial intima.
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PMID:Proteolysis and fusion of low density lipoprotein particles independently strengthen their binding to exocytosed mast cell granules. 829 53

The cause and consequence of altered proteoglycans in atherosclerosis are poorly understood. To determine whether proteoglycans affect monocyte binding, we studied the effects of heparin and proteoglycan degrading enzymes on THP-1 monocyte adhesion to subendothelial matrix (SEM). Monocyte binding increased about 2-fold after SEM was treated with heparinase. In addition, heparin decreased monocyte binding to fibronectin, a known SEM protein, by 60%. These data suggest that SEM heparan sulfate inhibits monocyte binding to SEM proteins. We next examined whether lysolecithin, a constituent of modified lipoproteins, affects endothelial heparan sulfate proteoglycan (HSPG) production and monocyte binding. Lysolecithin (10-200 microM) decreased total 35SO4 in SEM (20-75%). 2-fold more monocytes bound to SEM from lysolecithin treated cells than to control SEM. Heparinase treatment did not further increase monocyte binding to lysolecithin-treated SEM. HSPG degrading activity was found in medium from lysolecithin-treated but not control cells. 35SO4-labeled products obtained from labeled matrix treated with lysolecithin-conditioned medium were similar in size to those generated by heparinase. These data suggest that lysolecithin-treated endothelial cells secrete a heparanase-like activity. We hypothesize that decreased vessel wall HSPG, as occurs in atherogenic conditions, allows increased monocyte retention within the vessel and is due to the actions of an endothelial heparanase.
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PMID:Lysolecithin-induced alteration of subendothelial heparan sulfate proteoglycans increases monocyte binding to matrix. 853 Mar 67

Endothelial cell dysfunction is considered to be a critical event in the etiology of atherosclerosis. Thus, the preservation of endothelial structure and function are a prerequisite for normal control of vascular permeability properties, mediation of both inflammatory and immunologic responses and the general 'communication' between blood-borne cells and abluminal tissues. Many of these properties can be influenced by proteoglycans present in vascular tissues. There is evidence that selected lipids can be atherogenic by altering endothelial proteoglycan metabolism. Little is known about the role of fatty acids in modulating proteoglycan composition in endothelial cells. Data suggest, however, that linoleic acid in particular can adversely alter proteoglycan metabolism, which may be related to an imbalance in eicosanoid synthesis patterns. These events could be sufficient to disrupt normal endothelial barrier function, initiate smooth muscle migration and proliferation, and result in other metabolic dysfunctions associated with the etiology of vascular diseases such as atherosclerosis. Thus, the focus of this review is on fatty acids and eicosanoids as they may alter proteoglycan metabolism of vascular tissues and in particular of the endothelium.
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PMID:Role of fatty acids and eicosanoids in modulating proteoglycan metabolism in endothelial cells. 859 69


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