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)

An initial event in atherosclerosis is the retention of lipoproteins within the intima of the vessel wall. Previously we identified Site B (residues 3359-3369) in apolipoprotein (apo) B100 as the proteoglycan binding sequence in low density lipoproteins (LDLs) and showed that the atherogenicity of apoB-containing lipoproteins is linked to their affinity for artery wall proteoglycans. However, both apoB100- and apoB48-containing lipoproteins are equally atherogenic even though Site B lies in the carboxyl-terminal half of apoB100 and is absent in apoB48. If binding to proteoglycans is a key step in atherogenesis, apoB48-containing lipoproteins must bind to proteoglycans via other proteoglycan binding sites in the amino-terminal 48% of apoB. In vitro studies have identified five clusters of basic amino acids in delipidated apoB48 that bind negatively charged glycosaminoglycans. To determine which of these sites is functional on LDL particles, we analyzed the proteoglycan binding activity of recombinant human LDLs from transgenic mice or rat hepatoma cells. Substitution of neutral amino acids for the basic amino acids in Site B-Ib (residues 84-94) abolished the proteoglycan binding activity of recombinant apoB53. Carboxyl-truncated apoB80 bound biglycan with higher affinity than apoB100 and apoB48. ApoB80 in which Site B was mutated had the same affinity for proteoglycans as apoB48. These data support the hypothesis that the carboxyl terminus of apoB100 "masks" Site B-Ib, the amino-terminal proteoglycan binding site, and that this site is exposed in carboxyl-truncated forms of apoB. The presence of a proteoglycan binding site in the amino-terminal region of apoB may explain why apoB48- and apoB100-containing lipoproteins are equally atherogenic.
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PMID:Identification of the proteoglycan binding site in apolipoprotein B48. 1207 Jan 65

Proteoheparan sulphate can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. As a result of electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, thereby representing one receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques suggesting that high-density lipoprotein (HDL) has a high binding affinity and a protective effect on interfacial heparan sulphate proteoglycan layers with respect to low-density lipoprotein (LDL) and Ca2+ complexation. Low-density lipoprotein was found to deposit strongly at the proteoheparan sulphate-coated surface, particularly in the presence of Ca2+, apparently through complex formation 'proteoglycan-LDL-calcium'. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. On the other hand, HDL bound to heparan sulphate proteoglycan protected against LDL deposition and completely suppressed calcification of the proteoglycan-lipoprotein complex. In addition, HDL was able to decelerate the ternary complex deposition. Therefore, HDL attached to its proteoglycan receptor sites is thought to raise a multidomain barrier, selection and control motif for transmembrane and paracellular lipoprotein uptake into the arterial wall. Although much remains unclear regarding the mechanism of lipoprotein depositions at proteoglycan-coated surfaces, it seems clear that the use of such systems offers possibilities for investigating lipoprotein deposition at a 'nanoscopic' level under close to physiological conditions. In particular, Ca2+-promoted LDL deposition and the protective effect of HDL even at high Ca2+ and LDL concentrations agree well with previous clinical observations regarding risk and beneficial factors for early stages of atherosclerosis. Considering this, the system was tested on its reliability in a biosensor application in order to unveil possible acute pleiotropic effects of the lipid lowering drug fluvastatin. The very low-density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL)/LDL plasma fraction from a high risk patient with dyslipoproteinaemia and type 2 diabetes mellitus showed beginning arteriosclerotic nanoplaque formation already at a normal blood Ca2+ concentration, with a strong increase at higher Ca2+ concentrations. Fluvastatin, whether applied to the patient (one single 80 mg slow release matrix tablet) or acutely in the experiment (2.2 micromol L-1), markedly slowed down this process of ternary aggregational nanoplaque complexation at all Ca2+ concentrations used. This action resulted without any significant change in lipid concentrations of the patient. Furthermore, after ternary complex build-up, fluvastatin, similar to HDL, was able to reduce nanoplaque adsorption and size. These immediate effects of fluvastatin have to be taken into consideration while interpreting the clinical outcome of long-term studies.
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PMID:Biosensing of arteriosclerotic nanoplaque formation and interaction with an HMG-CoA reductase inhibitor. 1235 73

Retention of apolipoprotein (apo)B and apoE-containing lipoproteins by extracellular vascular proteoglycans is critical in atherogenesis. Moreover, high circulating apoC-III levels are associated with increased atherosclerosis risk. To test whether apoC-III content of apoB-containing lipoproteins affects their ability to bind to the vascular proteoglycan biglycan, we evaluated the impact of apoC-III on the interaction of [(35)S]SO(4)-biglycan derived from cultured arterial smooth muscle cells with lipoproteins obtained from individuals across a spectrum of lipid concentrations. The extent of biglycan binding correlated positively with apoC-III levels within VLDL (r = 0.78, P < 0.01), IDL (r = 0.67, P < 0.01), and LDL (r = 0.52, P < 0.05). Moreover, the biglycan binding of VLDL, IDL, and LDL was reduced after depletion of apoC-III-containing lipoprotein particles in plasma by anti-apoC-III immunoaffinity chromatography. Since apoC-III does not bind biglycan directly, enhanced biglycan binding may result from a conformational change associated with increased apo C-III content by which apoB and/or apoE become more accessible to proteoglycans. This may be an intrinsic property of lipoproteins, since exogenous apoC-III enrichment of LDL and VLDL did not increase binding. ApoC-III content may thus be a marker for lipoproteins characterized as having an increased ability to bind proteoglycans.
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PMID:ApoC-III content of apoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan. 1240 96

Chondroitin sulfate (CS) used for treatment of osteoarthritis exerts distinct effects on human articular chondrocytes in vitro. We performed a binding analysis with 99mTc-labeled CS (Condrosulf, a commercial CS preparation containing calcium stearate) and cultured human chondrocytes in order to evaluate the presence of specific receptors. Saturation binding at 37 degrees C for 2 h revealed the presence of high-affinity binding sites for CS with a Kd of 2.3 x 10(-9) mol/L and a Bmax of 5.0 x 10(8). Extensive dialysis of Chondrosulf led to a decrease of the binding affinity by 52.5 +/- 19.5% and of the number of CS binding sites/cell by 62.0 +/- 14.0%, demonstrating that the additive present in the Condrosulf preparation enhances CS binding. The nature of the binding site is not yet known but evidence exists in the literature that the scavenger receptor CD36, thoroughly investigated on macrophages, is also found on chondrocytes and might be involved in CS binding. Therefore, we undertook a comparative binding study with human monocytes and labelled LDL and oxidized LDL, the latter being a postulated atherogenic agent in atherosclerosis. For [125I]-LDL binding we found a Kd of 0.45 x 10(-8) mol/L and a Bmax of 0.14 x 10(6) on quiescent monocytes and for [125I]-(ox)LDL binding a Kd of 1.8 x 10(-8) mol/L and a Bmax of 1.3 x 10(6) using LPS-activated monocytes. These data are comparable to the binding affinity found for lipoprotein-proteoglycan-complexes and hence are an indication but not a proof that CD36 is involved in CS binding to human chondrocytes.
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PMID:Binding of [99mTc]chondroitin sulfate to scavenger receptors on human chondrocytes as compared to binding of oxidized [125I]LDL on human macrophages. 1250 34

Cadmium and lead are heavy metals that have been shown to induce vascular disorders such as atherosclerosis in experimental animals. However, little is known about the mechanisms by which cadmium and lead induce vascular toxicity. The toxicity was investigated using a culture system of vascular endothelial and smooth muscle cells. Cadmium destroys the monolayer of endothelial cells and the cytotoxicity is protected by zinc and copper without metallothionein induction. On the other hand, lead does not exhibit cytotoxicity but inhibits the repair of endothelial monolayers after wounding by a lower response to endogenous basic fibroblast growth factor mediated by suppression of the synthesis of perlecan, a large heparan sulfate proteoglycan. In addition, cadmium and lead reduce endothelial fibrinolytic activity by induction of plasminogen activator inhibitor type 1 synthesis and by inhibition of tissue-type plasminogen activator, respectively. In vascular smooth muscle cells, cadmium and lead can promote their proliferation and influence proteoglycan synthesis and fibrinolysis in different manners. These results indicate that cadmium and lead have specific toxicities in the proliferation, fibrinolysis, and extracellular matrix formation of vascular endothelial and smooth muscle cells.
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PMID:[Cell biology of heavy metal toxicity in vascular tissue]. 1504 28

Atherosclerosis is the formation of plaques in the arterial wall brought about by numerous events including the accumulation of oxidized low density lipoprotein (LDL), stimulation of inflammatory responses, the release of cytokines, and the attachment of monocytes to the arterial wall. Proteoglycans are implicated in many aspects of atherosclerosis including the metabolism of lipoproteins, regulation of cytokine activity, cell adhesion, and modification of the extracellular matrix. Due to their complex role in molecular recognition and cellular adhesion, the glycosaminoglycan (GAG) chains attached to the proteoglycan core and sialic acids on the terminal ends of the glycan chains are of interest. This study investigated the effects of exposure to transforming growth factor-beta 1 (TGF-beta 1) and tumor necrosis factor-a (TNF-a) on the expression of cell surface GAGs and sialic acids on human umbilical vein endothelial cells (HUVECs). Initial results show that TGF-beta 1 affected GAG expression compared to a control condition. Results also show that the combination of TGF-beta 1 and TNF-a affected GAG expression differently than does TGF-beta 1 alone. Additionally, TNF-a decreased the number of sialic acid residues per cell and TGF-beta 1 slightly upregulated sialic acid expression as compared to the control. The combination of the two cytokines showed a larger upward trend in this value. These data indicate that TNF-a and TGF-beta 1 play a role in the expression of GAG chains and sialic acids on the cell surface. Further study may clarify the implications of these findings for atherosclerosis.
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PMID:TGF-beta and TNF-a affect cell surface proteoglycan and sialic acid expression on vascular endothelial cells. 1513 80

The proteoglycan versican is one of several extracellular matrix (ECM) molecules that accumulate in lesions of atherosclerosis and restenosis. Its unique structural features create a highly interactive molecule that binds growth factors, enzymes, lipoproteins, and a variety of other ECM components to influence fundamental events involved in vascular disease. Versican is one of the principal genes that is upregulated after vascular injury and is a prominent component in stented and nonstented restenotic lesions. The synthesis of versican is highly regulated by specific growth factors and cytokines and the principal source of versican is the smooth muscle cell. Versican interacts with hyaluronan, a long chain glycosaminoglycan, to create expanded viscoelastic pericellular matrices that are required for arterial smooth muscle cell (ASMC) proliferation and migration. Versican is also prominent in advanced lesions of atherosclerosis, at the borders of lipid-filled necrotic cores as well as at the plaque-thrombus interface, suggesting roles in lipid accumulation, inflammation, and thrombosis. Versican influences the assembly of ECM and controls elastic fiber fibrillogenesis, which is of fundamental importance in ECM remodeling during vascular disease. Collectively, these studies highlight the critical importance of this specific ECM component in atherosclerosis and restenosis.
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PMID:Proteoglycans in atherosclerosis and restenosis: key roles for versican. 1514 69

The hypothesis that lipoprotein association with perlecan is atherogenic was tested by studying atherosclerosis in mice that had a heterozygous deletion of perlecan, the primary extracellular heparan sulfate proteoglycan in arteries. We first studied the expression of perlecan in mouse lesions and noted that this proteoglycan in aorta was found in the subendothelial matrix. Perlecan was also a major component of the lesional extracellular matrix. Mice with a heterozygous deletion had a reduction in arterial wall perlecan expression. Atherosclerosis in these mice was studied after crossing the defect into the apolipoprotein E (apoE) and LDL receptor knockout backgrounds. At 12 weeks, chow-fed apoE null mice with a heterozygous deletion had less atherosclerosis. However, at 24 weeks and in the LDL receptor heterozygous background, the presence of a perlecan knockout allele did not significantly alter lesion size. Thus, it appears that loss of perlecan leads to less atherosclerosis in early lesions. Although this might be attributable to a decrease in lipoprotein retention, it should be noted that perlecan might mediate multiple other processes that could, in sum, accelerate atherosclerosis.
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PMID:Atherosclerosis in perlecan heterozygous mice. 1525 95

The long-term success of cardiac allograft transplantation is limited by the development of a particular type of coronary atherosclerosis referred to as transplant vascular disease (TVD). Although the exact pathogenesis of TVD remains to be established, there is growing evidence that TVD involves immunological mechanisms operating in a milieu of nonimmunological risk factors. These immunological events constitute the principal initiating stimuli, resulting in endothelial injury with consequent myointimal hyperplasia, extracellular matrix synthesis and invocation of proteoglycan (PG)-lipoprotein interactions, leading, ultimately, to lipid retention in the vessel wall. The profound early 'insudation' of apolipoproteins along with uncertain endothelial 'intactness' in human coronary arteries in the transplanted heart, suggest that permeability of these vessel walls must be altered. Further, frequent and typically diffuse intracellular and extracellular accumulation of lipids and PGs in both the intimal and medial layers of cardiac allograft arteries has affirmed that the alloimmune environment accompanied with aberrant expression of extracellular matrix components, especially PGs, may strongly promote lipid imbibition in the allograft vascular bed, leading to TVD. In summary, the cumulative data support the view that profound lipid accumulation occurs in allograft arteries beginning very early post-transplantation, contributing to intimal thickening; that lipoproteins enter and are trapped in the subendothelial tissue, apparently through interactions with PGs; that with direct glycosaminoglycans, apolipoprotein interactions may occur, or they may occur through bridging molecules like phospholipase A2 and lipoprotein lipase; and that prolonged residence in the intima leads to lipoprotein modification, with subsequent modulation of biological processes that promote atherogenesis.
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PMID:Transplant vascular disease: role of lipids and proteoglycans. 1583 69

Lipoprotein retention on extracellular matrix (ECM) may play a central role in atherogenesis, and a specific extracellular matrix proteoglycan, biglycan, has been implicated in lipoprotein retention in human atherosclerosis. To test whether increased cellular biglycan expression results in increased retention of lipoproteins on ECM, rat aortic smooth muscle cells (SMCs) were transduced with a human biglycan cDNA-containing retroviral vector (LBSN) or with an empty retroviral vector (LXSN). To assess the importance of biglycan's glycosaminoglycan side chains in lipoprotein retention, ECM binding studies were also performed using RASMCs transduced with a retroviral vector encoding for a mutant, glycosaminoglycan-deficient biglycan (LBmutSN). Human biglycan mRNA and protein were confirmed in LBSN and LBmutSN RASMCs by Northern and Western blot analyses. HDL3+E binding to SMC ECM was increased significantly (as determined by 95% confidence intervals for binding curves) for LBSN as compared to either LXSN or LBmutSN cells; the increases for LBSN cell ECM were due primarily to an approximately 50% increase in binding sites (increased Bmax) versus LXSN cell ECM and of approximately 25% versus LBmutSN cell ECM. These results are consistent with the hypothesis that biglycan, through its glycosaminoglycan side chains, may mediate lipoprotein retention on atherosclerotic plaque ECM.
Atherosclerosis 2004 Nov
PMID:Smooth muscle cell biglycan overexpression results in increased lipoprotein retention on extracellular matrix: implications for the retention of lipoproteins in atherosclerosis. 1548 62


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