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)

The adsorption of a number of lipoproteins, i.e., low-density lipoprotein (LDL), oxidized LDL (oxLDL), high-density lipoprotein (HDL), and lipoprotein (a), at silica and methylated silica as well as at the latter surface modified through adsorption of proteoheparan sulfate, was investigated with in situ ellipsometry at close to physiological conditions. It was found that LDL, oxLDL, HDL, and lipoprotein (a) all adsorbed more extensively at silica than at methylated silica. Upon exposure of the methylated silica surface to proteoheparan sulfate, this proteoglycan adsorbs through its hydrophobic moiety, thereby forming a layer similar to that in the biological system, with the polysaccharide chains forming brushes oriented toward the aqueous solution. Analogous to the biological system, both lipoprotein (a) and LDL were found to deposit at such surfaces, the latter particularly in the simultaneous presence of Ca(2+). After HDL pre-exposure, however, no LDL deposition was observed, even at high LDL and Ca(2+) concentrations. These findings correlate well with those obtained from clinical investigations on risk factors for atherosclerosis. Copyright 2000 Academic Press.
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PMID:Ellipsometry Studies of Lipoprotein Adsorption. 1072 45

Group IIA secretory nonpancreatic phospholipase A(2) (snpPLA(2)) is associated with collagen fibers in the extracellular matrix of human atherosclerotic plaques. Decorin, a small proteoglycan (PG) carrying chondroitin/dermatan sulfate glycosaminoglycans (GAGs), forms part of the collagen network in human arteries. To explore whether snpPLA(2) may be associated with collagen fibers via interaction with decorin, we performed (1) immunohistochemistry to compare the relative in vivo localization of snpPLA(2) and decorin in human atherosclerotic tissue and (2) in vitro experiments to study the interaction between snpPLA(2) and decorin. In atherosclerotic lesions, decorin was detected within the snpPLA(2)-positive part of the intima close to the media. Electrophoretic mobility shift assay showed that snpPLA(2) binds to decorin synthesized by human fibroblasts. Native and GAG-depleted decorin enhanced the association of snpPLA(2) to collagen types I and VI in a solid-phase binding assay. Furthermore, snpPLA(2) bound efficiently to a recombinant decorin core protein fragment B/E (Asp45-Lys359). This binding was competed with soluble decorin and inhibited at NaCl concentrations >150 mmol/L. The decorin core protein fragment B/E competed better than dermatan sulfate for binding of snpPLA(2) to decorin-coated microtiter wells. The enzymatic activity of snpPLA(2) increased 2- to 3-fold in the presence of decorin or GAG-depleted decorin. The results show that snpPLA(2) binds preferentially to the decorin protein core rather than to the GAG chain and that this interaction enhances snpPLA(2) activity. As a consequence, this active extracellular enzyme may contribute to the pathogenesis of atherosclerosis by modifying lipoproteins and releasing inflammatory lipid mediators at places of lipoprotein retention in the arterial wall.
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PMID:Molecular basis for the association of group IIA phospholipase A(2) and decorin in human atherosclerotic lesions. 1074 93

Inflammation may contribute to the pathogenesis of atherosclerosis. On the basis of previous reports that human atherosclerotic lesions contain alpha-defensins, a class of cationic proteins released by activated neutrophils, the study was designed to ask whether defensins modulate the binding and catabolism of low-density lipoprotein (LDL) by human vascular cells. The results of the study demonstrated that defensin stimulated the binding of (125)I-LDL to cultured human umbilical vein endothelial cells, smooth muscle cells, and fibroblasts approximately 5-fold in a dose-dependent and saturable manner. Defensin and LDL formed stable complexes in solution and on cell surfaces. Stimulation of LDL binding by defensin was not inhibited by antibodies against the LDL-receptor (LDL-R), or by recombinant receptor-associated protein, which blocks binding of ligands to the alpha(2)-macroglobulin receptor/LDL-R-related protein and other LDL-R family members. Furthermore, defensin stimulated the binding, endocytosis, and degradation of LDL by fibroblasts lacking LDL-R. Stimulation of LDL degradation by defensin was inhibited approximately 75% by low concentrations of heparin (0.2 units/mL) and was similarly reduced in CHO cells lacking heparan-sulfate-containing proteoglycans. The effect of defensin was substantially increased in cells overexpressing the core protein of the syndecan-1 heparan sulfate proteoglycan. The alpha-defensins released from activated neutrophils may provide a link between inflammation and atherosclerosis by changing the pattern of LDL catabolism from LDL-R to the less efficient LDL-R-independent, proteoglycan-dependent pathway. (Blood. 2000;96:1393-1398)
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PMID:The alpha-defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells: a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis. 1094 83

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

Lipoprotein-matrix interactions play an important role in arterial disease. Extracellular matrix proteoglycans bind and retain specific positively charged domains on apolipoproteins B- and E-containing lipoproteins during atherogenesis. Retained lipoproteins can undergo several modifications, which may alter their interaction with extracellular matrix molecules. Growth factors, cytokines and oxidized low density lipoproteins influence proteoglycan structure, rendering them more likely to bind and retain lipoproteins during atherogenesis. Lipoproteins, native and modified, also can modulate the expression of several of the matrix degrading enzymes present in vascular tissue, thereby influencing plaque stability. Thus, the interaction of atherogenic lipoproteins with arterial wall matrix molecules can influence the genesis and progression of atherosclerosis and its complications.
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PMID:Interaction of native and modified low-density lipoproteins with extracellular matrix. 1104 88

Abdominal aortic aneurysm (AAA) is a common disease of human aorta with increased incidence. It is a complication to atherosclerosis and it is closely associated with alterations in extracellular macromolecules. In this study, the levels of mRNA for versican--the major extracellular arterial proteoglycan (PG)--present in AAA and normal aortas were evaluated by reverse-transcriptase polymerase chain reaction. The concentration of versican was also examined in corresponding tissue samples. Versican was almost completely extracted with 4 M guanidine hydrochloride in the presence of Triton X-100, isolated by chromatography on DEAE-Sephacel and characterized using treatment with specific chondro-/dermato-lyases and agarose gel electrophoresis. Versican localization in tissue as well as the variation and distribution of smooth muscle cells (SMCs) and macrophages were also investigated immunohistochemically. The mRNAs coding for versican isoforms V(0) and V(1) were identified in both tissues, whereas V(2) was absent. The expression of V(0) was decreased 40% in aneurysmal vessel wall, whereas that for V(1) remained constant. This change was simultaneous with a significant decrease in versican concentration by 89%. In normal aortas, most versican was seen in the intima, whereas in AAA, this layer is characterized by advanced atherosclerotic lesion, rich in lipids and macrophages but poor in versican. The decreased transcription and the still lower amount of versican in the AAA may correlate to (i) a decrease in density of SMCs, these cells being the major source of versican in aorta, and (ii) the presence of macrophages, which may induce versican degradation and modulate versican synthesis. It is proposed that the decreased synthesis and increased degradation of versican, particularly of isoform V(0), and the resulting low concentration in the intima are crucial factors contributing to the altered viscoelastic and compressive properties and thereby to the deformity and dilatation of aorta.
Atherosclerosis 2001 Feb 01
PMID:Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V(0). 1116 69

Degranulated mast cells are present in the human arterial intima. After degranulation of rat serosal mast cells, the secreted neutral serine protease chymase remains bound to the heparin proteoglycan matrix of the exocytosed granules, forming granule remnants. Addition of granule remnants to human aortic intimal fluid results in proteolysis of the apoAI present in the intimal fluid, which contains physiological inhibitors of chymase. To study the physiological mechanism of this protection of granule remnant-bound chymase against its inhibitors, we performed experiments using HDL3 as substrate. Chymase, when bound to the heparin proteoglycans of granule remnants, but not when released from them, resisted inhibition by the mammalian protease inhibitors alpha1-antitrypsin, alpha2-antichymotrypsin, alpha2-macroglobulin, and eglin C. Importantly, the heparin proteoglycan-bound chymase, but not unbound chymase, degraded its inhibitor (alpha1-antitrypsin) in the presence of its substrate (HDL3). Finally, binding to heparin proteoglycans of a physiological inhibitor of chymase (mucus protease inhibitor (MPI)) or of another substrate of chymase (LDL) did not inhibit the degradation of HDL3 by granule remnant-bound chymase. This study demonstrates that binding of chymase to the heparin proteoglycan chains of the exocytosed mast cell granules allows the protease to remain active and degrade HDL3 in the presence of its physiological inhibitors and in the presence of high concentrations of LDL, such as are found in the interstitial fluid of the arterial intima.
Atherosclerosis 2001 Mar
PMID:Chymase bound to heparin is resistant to its natural inhibitors and capable of proteolyzing high density lipoproteins in aortic intimal fluid. 1122 30

Decorin is a member of the family of small leucine-rich proteoglycans that are present in blood vessels and synthesized by arterial smooth muscle cells (ASMCs). This proteoglycan accumulates in topographically defined regions of atherosclerotic lesions and may play a role in the development of this disease. However, little is known about whether decorin has specific effects on the cellular events that contribute to atherosclerotic lesion formation. In the present study, rat ASMCs were transduced with a retroviral vector (LDSN) that carries the bovine decorin gene. Compared with vector control cells (LXSN), these cells constitutively overexpress decorin, as verified by Northern and Western analysis and by metabolic labeling. Experiments were performed to examine the responsiveness of decorin-overexpressing rat ASMCs to platelet-derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1), 2 growth factors that affect cell proliferation and extracellular matrix production in atherosclerosis. Decorin-overexpressing cells had decreased [(3)H]thymidine incorporation into DNA and increased the levels of the cyclin-dependent kinase inhibitors p21 and p27 in the first 24 hours of response to serum and PDGF-BB. However, these effects of decorin were not apparent at 48 or 72 hours after plating and did not result in reduced growth of decorin-overexpressing cells in response to serum and PDGF-BB. In contrast, the growth response of decorin-overexpressing ASMCs to TGF-beta1, as well as the expression of TGF-beta1-responsive genes, such as plasminogen activator inhibitor-1 and versican (an extracellular matrix proteoglycan), was diminished. These results indicate that decorin selectively inhibits the responsiveness of rat ASMCs to TGF-beta1 and suggests that the induction of constitutive decorin overexpression by ASMCs in vivo may have therapeutic value in the inhibition of TGF-beta1-mediated effects on the development of atherosclerotic lesions.
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PMID:Retroviral overexpression of decorin differentially affects the response of arterial smooth muscle cells to growth factors. 1134 74

The first morphological sign of atherogenesis is the accumulation of extracellular lipid droplets in the proteoglycan-rich subendothelial layer of the arterial intima. Secretory nonpancreatic phospholipase A(2) (snpPLA(2)), an enzyme capable of lipolyzing LDL particles, is found in the arterial extracellular matrix and in contact with the extracellular lipid droplets. We have recently shown that in the presence of heparin, lipolysis of LDL with bee venom PLA(2) induces aggregation and fusion of the particles. Here, we studied the effect of human snpPLA(2) on the integrity of LDL particles and on their interaction with human aortic proteoglycans. In addition, the capacity of the proteoglycans to retain PLA(2)-lipolyzed LDL particles was tested in a microtiter well assay. We found that lipolysis of LDL induced fusion of proteoglycan-bound LDL particles, which increased their binding strength to the proteoglycans. Moreover, lipolysis of LDL with snpPLA(2) under physiological salt and albumin concentrations induced a 3-fold increase in the amount of LDL bound to proteoglycans. The results imply a role for PLA(2) in the retention and accumulation of LDL to the proteoglycan matrix in atherosclerosis.
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PMID:Lipolysis of LDL by human secretory phospholipase A(2) induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. 1139 92

Calcium channel blockers are known to retard atherosclerosis. In this study, we tested the hypothesis that one mechanism by which calcium channel blockers retard atherosclerosis is through the modulation of proteoglycan metabolism by vascular smooth muscle cells. We investigated the effect of amlodipine and nifedipine on proteoglycan synthesis by human aortic smooth muscle cells and the ability of the newly synthesized proteoglycans to bind low density lipoprotein (LDL). Confluent smooth muscle cells were incubated with [(35)S]sulfate alone or [(35)S]sulfate and [(3)H]leucine in the presence and absence of different concentrations of amlodipine and nifedipine (0.1--20 microg/ml) for 24 h, and newly synthesized proteoglycans were analyzed. Both amlodipine and nifedipine inhibited proteoglycan synthesis by smooth muscle cells in a dose-dependent manner; however, amlodipine was significantly more potent than nifedipine in this regard. In the presence of 20 microg/ml amlodipine, media and cellular proteoglycans decreased by 56%. This was due to inhibition of de novo proteoglycan synthesis by amlodipine. Compared with the proteoglycans synthesized by control smooth muscle cells, those synthesized by cells exposed to amlodipine were smaller and less sulfated, and contained fewer glycosaminoglycan chains. In addition, proteoglycans synthesized by cells treated with amlodipine bound LDL with low affinity. These results suggest that amlodipine may protect against atherosclerosis through a proteoglycan-mediated mechanism.
Atherosclerosis 2001 Aug
PMID:Effect of calcium channel blockers on proteoglycan synthesis by vascular smooth muscle cells and low density lipoprotein--proteoglycan interaction. 1147 34


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