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)

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

Dermatan sulfate proteoglycans (DSPG) were extracted from intima-media of grossly normal aortic tissue of White Carneau pigeons and were purified by ion exchange chromatography on DEAE-Sephacel followed by size exclusion chromatography on Sepharose CL-4B. The major aortic DSPG had an average size of 310 kDa. The core protein resulting from treatment of the PG with chondroitinase ABC: (1) was found to be approximately 48 kDa by SDS-polyacrylamide gel electrophoresis; (2) was recognized by monoclonal antibody (Mab) 2-B-6 but not by Mab 3-B-3 on Western blots, indicating the presence of delta Di-4S and absence of delta Di-6S; (3) was glycosylated with Asn-linked oligosaccharides; (4) contained a high content of Asx, Glx and Leu, similar to that found for core proteins of this size from other tissues and species and (5) contained an N-terminal sequence (Asp-Glu-Gly-Xaa-Ala-Asp-Met-Pro-Pro-Xaa-Asp-Asp-Pro-Val- Ile-(ile)-Gly-Phe-), which was similar to sequences of DSPG core proteins previously described as 'decorin' and distinct from DSPG described as 'biglycan'. The results suggest that the major DSPG of aorta can be classified as a decorin molecule. The overall size of the DSPG in aorta was larger than decorin molecules described in non-arterial tissues of other species. Evidence is presented to conclude the larger size results from more than one dermatan sulfate-glycosaminoglycan chain.
Atherosclerosis 1993 Jan 04
PMID:Structural properties and partial protein sequence analysis of the major dermatan sulfate proteoglycan of pigeon aorta. 845 55

Compared to cholesterol or linoleic acid (18:2), oxidized lipids such as cholestan-3 beta, 5 alpha, 6 beta-triol (triol) and hydroperoxy linoleic acid (HPODE) markedly impair endothelial barrier function in culture [Hennig and Boissonneault, 1987; Hennig et al. 1986]. Because proteoglycans contribute to vascular permeability properties, the effects of cholesterol and 18:2 and their oxidation products, triol and HPODE, on endothelial proteoglycan metabolism were determined. While cholesterol was without effect, a concentration-dependent decrease in cellular proteoglycans (measured by 35S incorporation) was observed after exposure to triol. Compared to control cultures, cholesterol reduced mRNA levels for the proteoglycans, perlecan and biglycan. Triol had a similar effect on biglycan but not an perlecan mRNA levels. Compared to 18:2, 1,3 and 5 microM HPODE depressed cellular proteoglycans. Perlecan mRNA levels were reduced more by HPODE when compared to 18:2. Biglycan mRNA levels were reduced by 3 microM, but not by 5 microM HPODE. These data demonstrate that oxidized lipids such as triol and HPODE can decrease cellular proteoglycan metabolism in endothelial monolayers and alter mRNA levels of major specific proteoglycans in a concentration-dependent manner. This may have implications in lipid-mediated disruption of endothelial barrier function and atherosclerosis.
Atherosclerosis 1996 Feb
PMID:Oxidized lipid-mediated alterations in proteoglycan metabolism in cultured pulmonary endothelial cells. 864 61

The small leucine-rich proteoglycan biglycan is involved in several physiological and pathophysiological processes through the ability of its core protein to interact with other extracellular matrix molecules and transforming growth factor-beta (TGF-beta). To learn more about the regulation of biglycan core protein expression, we have cloned and sequenced 1218 base pairs from the 5'-flanking region of the human biglycan gene, demonstrated functional promoter activity, and investigated the molecular mechanisms through which various agents modulate its transcriptional activity. Sequencing revealed the presence of several cis-acting elements including multiple AP-2 sites and interleukin-6 response elements, a NF-kappaB site, a TGF-beta negative element, and an E-box. The TATA and CAAT box-lacking promoter possesses many features of a growth-related gene, e.g. a GC-rich immediate 5' region, many Sp1 sites, and the use of multiple transcriptional start sites. Transient transfections of the tumor cell lines MG-63, SK-UT-1, and T47D with various biglycan 5'-flanking region-luciferase reporter gene constructs showed that the proximal 78 base pairs are sufficient for full promoter activity. Several agents among them interleukin-6, and tumor necrosis factor-alpha. were capable of altering biglycan promoter activity. However, in MG-63 cells, TGF-beta1 failed to increase either activity of the biglycan promoter constructs or specific transcription from the endogenous biglycan gene. Since TGF-beta1 also did not alter the stability of cytoplasmic biglycan mRNA as determined from Northern analysis after inhibition of transcription with 5,6-dichloro-1beta-D-ribofuranosylbenzimidazole, an as yet unidentified nuclear post-transcriptional mechanism was considered responsible for the TGF-beta effect in this cell type. These results might help to elucidate the molecular pathways leading to pathological alterations of biglycan expression observed in atherosclerosis, glomerulonephritis, and fibrosis.
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PMID:Transcriptional regulation of the human biglycan gene. 866 74

Smooth muscle cell (SMC) proliferation and increased production of arterial wall proteoglycans (PG) are implicated in atherogenesis. We investigated the effect of SMC proliferation on the biosynthesis of PG and the ability of the newly synthesized PG to bind low density lipoprotein (LDL). Proliferating and quiescent human aortic SMC were pulsed with [35S]sulfate for 24 h. Secreted and cell-associated PG were then analyzed. When SMC plated at a low density were induced to proliferate, PG synthesis increased significantly in comparison with quiescent cells. This was the net result of a 2.7-fold increase in secreted PG and a 1.3-fold increase in cell-associated PG. The increased PG synthesis in proliferating SMC correlated with a significant increase in the steady-state level of mRNA for perlecan and biglycan, and a modest increase in the versican-specific mRNA. The mRNA for decorin showed a 40% decrease. The increased PG secretion in proliferating cultures was due to increases in heparan sulfate PG, dermatan sulfate PG, and chondroitin sulfate PG secretion. Quiescent SMC at confluency produced 50% less PG than the corresponding SMC plated at a low density. Although confluent SMC stimulated to proliferate also had increased PG synthesis, this was 50% less than the PG synthesis by proliferating SMC that were initially plated at a low density. The PG synthesized by proliferating and quiescent SMC did not differ in charge density and molecular size. Secreted PG from both quiescent and proliferating cultures contained subfractions that bound LDL with high affinity. However, compared with quiescent cultures, the proliferating cultures produced more of a PG subfraction that exhibited very high affinity to LDL (31.6% in quiescent cultures versus 40.8% in proliferating cultures). These results indicate that PG metabolism is altered significantly in proliferating human SMC which might have implications in the pathophysiology of atherosclerosis.
Atherosclerosis 1997 Dec
PMID:Elevated expression of proteoglycans in proliferating vascular smooth muscle cells. 943 Mar 66

The accumulation of proteoglycans (PGs) in atherosclerosis contributes to disease progression and stenosis and may partly depend on local regulation by growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta. In this study, the distribution of the major extracellular PGs is compared with that of PDGF and TGF-beta isoforms in developing lesions of atherosclerosis from hypercholesterolemic nonhuman primates. Strong immunostaining for decorin, biglycan, versican, and hyaluronan is observed in both intermediate and advanced lesions. Perlecan staining is weak in intermediate lesions but strong in advanced lesions in areas bordering the plaque core. Immunostaining for PDGF-B and TGF-beta1 is particularly prominent in macrophages in intermediate and advanced lesions. In contrast, TGF-beta2 and TGF-beta3 and PDGF-A are present in both macrophages and smooth muscle cells. Overall, PG deposits parallel areas of intense growth factor immunostaining, with trends in relative localization that suggest interrelationships among certain PGs and growth factors. Notably, decorin and TGF-beta1 are distributed similarly, predominantly in the macrophage-rich core, whereas biglycan is prominent in the smooth muscle cell matrix adjoining TGF-beta1-positive macrophages. Versican and hyaluronan are enriched in the extracellular matrix adjacent to both PDGF- and TGF-beta1-positive cells. These data demonstrate that PG accumulation varies with lesion severity, structural characteristics, and the proximity of PDGF and TGF-beta.
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PMID:Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. 946 80

We recently reported the presence of secretory, nonpancreatic phospholipase A2 type II (snpPLA2; EC 3.1.1.4) in human atherosclerotic arteries (Hurt-Camejo et al, Arterioscler Thromb Vasc Biol. 1997;17:300-309). SnpPLA2 may generate the proinflammatory products lysophospholipids and free fatty acids, thus contributing to atherogenesis when acting on low density lipoproteins (LDLs) retained in the arterial wall. Immunohistochemical studies showed that smooth muscle cells (SMCs) in human arterial tissue are the main sources of snpPLA2. In cultures of human arterial SMCs, snpPLA2 interacts with versican and smaller heparan/chondroitin sulfate proteoglycans (PGs) secreted as soluble components into the medium. In the present study, we investigated the binding of snpPLA2 to extracellular matrix (ECM) PGs produced by SMCs. The results show that snpPLA2 can bind to the ECM at physiological salt concentrations. ECM-bound snpPLA2 was active, hydrolyzing phosphatidylcholine-containing micelles. Soluble chondroitin-6-sulfate at concentrations >1 micromol/L, but not heparin or heparan sulfate, was able to release ECM-bound snpPLA2. The PG mainly involved in the binding of snpPLA2 was identified as biglycan. Perlecan was also present in the ECM synthesized by SMCs, but it contributed less to the binding of snpPLA2. Experiments with immobilized glycosaminoglycans indicated that snpPLA2 hydrolyzed 7-fold more LDL phospholipids when the lipoprotein and the enzyme were colocalized in a matrix with chondroitin-6-sulfate compared with one with heparin. These data suggest that retention of snpPLA2 in ECMs of different composition may modulate the enzymatic activity of snpPLA2 toward LDL. The results presented in this work support the hypothesis of the potential contribution of snpPLA2 to atherosclerosis.
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PMID:Phospholipase A2 type II binds to extracellular matrix biglycan: modulation of its activity on LDL by colocalization in glycosaminoglycan matrixes. 984 87

Proteoglycans decorin and biglycan, which bind to TGF-beta, are thought to participate in regulation of extracellular matrix accumulation in arterial intimal hyperplasia. To investigate the correlation of these proteoglycans with the cellular localization and phenotypic modulation of smooth muscle cells (SMCs), we analyzed the spatial and chronological distribution of these proteoglycans and two cytokines, TGF-beta and IL-1beta, in the process of neointima formation after stent implantation in the aortas of rabbits fed a high-cholesterol diet (atherosclerotic group) or a regular diet (control group). We implanted metallic stents in the rabbit aortas and harvested the aortas 4-56 days later for immunohistochemical and mRNA in situ hybridization analyses. In the control group, TGF-beta and biglycan expression was in correspondence with the chronology and localization of embryonic SMCs. In the atherosclerotic group, TGF-beta and biglycan expression was sustained throughout the experimental period, which was in accord with the prolonged expression of embryonic SMCs. Decorin, which did not occur in neointima in the control group, appeared in the atherosclerotic aortas in the confined area of vascular SMCs surrounding the macrophages around the stent wire. These results indicate that biglycan and decorin kinetics during neointima formation after arterial injury are distinct, despite their similar construction; biglycan synthesis correlates with embryonic SMCs.
Atherosclerosis 2000 Oct
PMID:Differential expression of proteoglycans biglycan and decorin during neointima formation after stent implantation in normal and atherosclerotic rabbit aortas. 1099 56

Proteoglycans (PGs), especially chondroitin/dermatan sulfate proteoglycans (CS/DSPGs), accumulate and their composition variously changes in atherosclerotic vascular walls. Since cadmium causes atherosclerosis in experimental animals, PGs synthesized by cultured vascular smooth muscle cells after exposure to cadmium were characterized in the present study. Sparse and dense cultures of the cells were metabolically labeled with [35S]sulfate for 24 h in the presence of cadmium chloride at noncytotoxic levels (0.2 microM or less). The incorporation of [35S]sulfate into glycosaminoglycans was determined by the cetylpyridinium chloride precipitation method. The labeled PGs were characterized by DEAE-Sephacel ion exchange chromatography and Sepharose CL-4B molecular sieve chromatography. The M(r) and the glycosaminoglycan composition of small CS/DSPGs were analyzed by SDS-polyacrylamide gel electrophoresis and Sepharose CL-6B chromatography, respectively, before and after digestion with chondroitin ABC lyase or papain. The core proteins were identified by Western blot analysis. These experiments indicate that cadmium differentially acts on the PG synthesis when vascular smooth muscle cell density is low. Specifically, cadmium increased the accumulation of small CS/DSPGs identified as biglycan and decorin in the cell layer of sparse cells. However, the hydrodynamic size and the length of chondroitin/dermatan sulfate chains in the PGs were unaffected by cadmium. On the other hand, cadmium decreased other cell layer-associated PGs that were separated from biglycan and decorin by DEAE-Sephacel chromatography in the sparse cells; as the result, whole glycosaminoglycans were decreased in both the cell layer and the conditioned medium. It is therefore concluded that cadmium may change the composition of PGs in atherosclerotic plaques through induction of biglycan and decorin synthesis and inhibition of other PG synthesis in vascular smooth muscle cells.
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PMID:Differential effects of cadmium on proteoglycan synthesis of arterial smooth muscle cells: increase in small dermatan sulfate proteoglycans, biglycan and decorin, in the extracellular matrix at low cell density. 1175 86

Retention of atherogenic apolipoprotein (apo) B- and E- containing lipoproteins by their interaction with arterial wall proteoglycans is important in atherogenesis. Levels of triglyceride (TG)-rich lipoproteins, which contain both apo B and apo E, are increased in type 2 diabetes. Because increased retention of TG-rich lipoproteins in diabetes might explain, in part, the increased atherosclerosis in this disorder, TG-rich lipoproteins were isolated from fasting type 2 diabetic subjects and age-matched controls, and assessed for their ability to bind biglycan, a vascular smooth muscle cell-derived proteoglycan. The binding of TG-rich lipoproteins isolated from diabetic subjects to purified biglycan did not differ from lipoproteins isolated from control subjects. Moreover, contrary to previous reports, no difference in the apo E content of TG-rich lipoproteins was detected between the control and diabetic groups. Additionally, no difference in the binding affinity of TG-rich lipoproteins for the low-density lipoprotein receptor was observed between control and diabetic subjects. Thus, we were unable to confirm previous reports that TG-rich lipoproteins from subjects with diabetes are enriched in apo E compared with age-matched controls, consistent with the lack of difference in binding of these lipoproteins to either biglycan or the low-density lipoprotein receptor. Therefore, increased affinity of TG-rich lipoproteins for biglycan is unlikely to explain the increased atherosclerosis in type 2 diabetes.
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PMID:Triglyceride-rich lipoproteins from subjects with type 2 diabetes do not demonstrate increased binding to biglycan, a vascular proteoglycan. 1178 18


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