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)

Proteoheparan sulfate can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. Due to electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, representing a receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques showing that HDL has a high binding affinity to the receptor and a protective effect on interfacial heparan sulfate proteoglycan layers, with respect to LDL and Ca(2+) complexation. LDL was found to deposit strongly at the proteoheparan sulfate, particularly in the presence of Ca(2+), thus creating the complex formation "proteoglycan-low density lipoprotein-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 sulfate proteoglycan protected against LDL docking and completely suppressed calcification of the proteoglycan-lipoprotein complex. In addition, HDL and aqueous garlic extract were able to reduce the ternary complex deposition and to disintegrate HS-PG/LDL/Ca(2+) aggregates. 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, Ca(2+)-promoted LDL deposition and the protective effect of HDL, even at high Ca(2+) and LDL concentrations, agree well with previous clinical observations regarding risk and beneficial factors for early stages of atherosclerosis. Therefore, we believe that the system can be of some use in investigations, e.g. of the interplay between different lipoproteins in arteriosclerotic plaque formation, as well as in high throughput screening of candidate drugs to atherosclerosis in a biosensor application.
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PMID:A receptor-based biosensor for lipoprotein docking at the endothelial surface and vascular matrix. 1167 68

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

Atherosclerosis is the main cause of morbidity and mortality in diabetes, yet the underlying mechanisms remain unclear. Retention of atherogenic lipoproteins by vascular proteoglycans is thought to play a key role in the development of atherosclerotic lesions. High glucose levels cause a variety of diabetic complications by several mechanisms, including upregulation of the hexosamine pathway. Glucosamine, a component of the hexosamine pathway, is a precursor for the synthesis of glycosaminoglycan components of proteoglycans. This study evaluated whether high glucose or glucosamine supplementation of vascular smooth muscle cells would increase proteoglycan synthesis, leading to increased lipoprotein retention. Aortic smooth muscle cells were exposed to physiologic (5.6 mM) or high (25 mM) glucose levels, such as seen in diabetes, or to glucosamine (12 mM). Extracellular proteoglycans were characterized by sulfate incorporation, molecular sieve chromatography, and SDS-PAGE. LDL interactions were assessed by affinity chromatography and gel mobility shift assay. Proteoglycans synthesized in the presence of high glucose demonstrated no differences in size, sulfate incorporation, or LDL binding affinity compared with proteoglycans synthesized under physiological glucose conditions. However, proteoglycans synthesized in the presence of glucosamine had smaller glycosaminoglycan chains than control proteoglycans with a corresponding decrease in lipoprotein retention.Thus, glucose and glucosamine have different effects on proteoglycan biosynthesis and different effects on lipoprotein retention.
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PMID:Arterial smooth muscle cell proteoglycans synthesized in the presence of glucosamine demonstrate reduced binding to LDL. 1179 34

Proteoglycan accumulation within the arterial intima has been implicated in lipoprotein retention and in atherosclerosis progression in humans. Two commonly studied murine models of atherosclerosis, the apolipoprotein E (apoE)-deficient (apoE-/-) mouse and the low density lipoprotein receptor-deficient (LDLR-/-) mouse, develop arterial lesions similar to those of human atherosclerosis. However, specific proteoglycan classes that accumulate in lesions of these mice and their relation to the retention of specific apolipoproteins have not been previously determined. In this report, we characterized the distribution of proteoglycans (versican, biglycan, and perlecan) and apolipoproteins (apoB, apoA-I, and apoE) in proximal aortic lesions of chow-fed apoE-/- and LDLR-/- mice at 10, 52, and 73 weeks of age. We observed that similar to the apoE-/- mice, the LDLR-/- mice develop intermediate and advanced plaques within 52 weeks of age. Perlecan and biglycan (both are proteoglycans) appeared early in lesion development with distinct expression patterns as the plaques advanced. Versican, a major proteoglycan detected in human plaques, was mostly absent in both strains. ApoA-I and apoB were detected in early through advanced lesions in regions of proteoglycan accumulation in both strains. Our results indicate that proteoglycans may contribute to the retention of lipoproteins at the earliest stage of atherosclerosis in murine models of atherosclerosis.
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PMID:Accumulation of biglycan and perlecan, but not versican, in lesions of murine models of atherosclerosis. 1188 91

Lumican is a member of a small leucine-rich proteoglycan family. Members of this family play an important role in cell migration and proliferation during embryonic development, tissue repair, and tumor growth. Lumican is reported to be overexpressed during the wound-healing process in the cornea and ischemic and reperfused heart. Recently, we found that lumican mRNA and its protein are expressed in cultured vascular smooth muscle cells (VSMCs) from the rat aorta. However, the expression and role of lumican in human atherosclerotic tissues are not clearly elucidated. In the present study, we aimed to clarify whether lumican is expressed in VSMCs and its localization in human coronary atherosclerotic tissues. The lumican protein and its mRNA were expressed in a small number of VSMCs in the media of normal coronary artery, but the lumican protein was not localized in the medial stroma. In contrast, the lumican protein and its mRNA were expressed in most of VSMCs that migrated into the thickened intima, but not in infiltrating foamy macrophages. The lumican protein was prominently localized in the thickened intimal stroma. The lumican protein and its mRNA were also expressed in VSMCs in the inner layer of the media and its protein was localized in medial stromal tissues. These findings indicate that the lumican protein is mainly synthesized by intimal and medial VSMCs in coronary atherosclerosis and that lumican contributes to collagen fibrillogenesis of coronary atherosclerosis.
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PMID:Expression of lumican in thickened intima and smooth muscle cells in human coronary atherosclerosis. 1189 Jul 23

The aim of this study was to determine, if gemfibrozil has anti-atherogenic actions on human vascular smooth muscle cells (SMCs) and whether these actions are affected by high glucose concentrations, which mimic the hyperglycemia of diabetes. Proliferation of SMCs treated with gemfibrozil was estimated by cell counting (Coulter Counter) and [3H]thymidine incorporation, migration in a scrape-wound assay, proteoglycan (PG) biosynthesis and glycosaminoglycan (GAG) synthesis on xyloside by [35S]sulfate labeling and sizing by sodium dodecyl sulphide-polyacrylamide gel electrophoresis (SDS-PAGE). Gemfibrozil (100 micromol/l) did not affect migration in low or high glucose media. Gemfibrozil caused concentration-dependent inhibition of proliferation in low glucose media (24% inhibition at 100 micromol/l, P<0.01) and inhibited the re-initiation of DNA synthesis by 33.3% (100 micromol/l, P<0.05) in low glucose and 31.4% (100 micromol/l, P<0.001) in high glucose conditions. In low and high glucose media, gemfibrozil (100 micromol/l) reduced total PG production in the presence of TGF-beta 1, which was associated with a decrease in the apparent size of PGs. Gemfibrozil and another PPAR-alpha ligand, WY-14643, significantly inhibited basal and TGF-beta1 stimulated GAG synthesis. We conclude that some SMCs properties associated with atherogenesis are favorably affected by gemfibrozil. Hence, direct vascular actions of gemfibrozil observed in this study may contribute to the reduction in cardiovascular disease observed in clinical studies with gemfibrozil.
Atherosclerosis 2002 May
PMID:Differential effects of gemfibrozil on migration, proliferation and proteoglycan production in human vascular smooth muscle cells. 1194 5

One mechanism by which Angiotensin II (AII) may promote atherogenesis is through modulation of proteoglycan (PG) metabolism by vascular smooth muscle cells (SMC). To test this hypothesis, we investigated the effect of AII on PG synthesis by human aortic SMC and the ability of the newly synthesized PG to bind low density lipoprotein (LDL). AII stimulated PG synthesis by SMC in a dose- and time-dependent manner. In the presence of 1 microM AII, medium and cellular PG increased by 73 and 97%, respectively. AII caused a 55% increase in biglycan mRNA which resulted in a 52% increase in biglycan synthesis. Losartan, an AII receptor antagonist, and broad and isoform-specific protein kinase C (PKC) inhibitors abolished the AII-induced up-regulation of PG synthesis. Moreover, direct activation of PKC with phorbol ester stimulated PG synthesis significantly. Similarly, inhibitors of tyrosine kinase also caused inhibition of PG synthesis. AII increased the size and charge density of the newly synthesized PG. In addition, AII stimulated the synthesis of PG that bound LDL with very high affinity by 2.5-fold to 3-fold over control. These results suggest that the AII-mediated alterations in vascular SMC PG metabolism may contribute to the pathophysiology of atherosclerosis.
Atherosclerosis 2002 Jun
PMID:Angiotensin II stimulates synthesis of vascular smooth muscle cell proteoglycans with enhanced low density lipoprotein binding properties. 1199 45

Blood vessel cells express the 2 known estrogen receptors, alpha and beta (ERalpha, ERbeta), which are thought to mediate estrogen inhibition of vascular injury and atherosclerosis, but the relative role of ERalpha and ERbeta in these events is controversial. Estrogen inhibits the vascular injury response to the same extent in ovariectomized female wild-type mice and in the original single gene knockout mice for ERalpha (ERalphaKO(Chapel Hill) [ERalphaKO(CH)]) and ERbeta (ERbetaKO(Chapel Hill) [ERbetaKO(CH)]). In double gene knockout mice generated by crossing these animals (ERalpha,betaKO(CH)), estrogen no longer inhibits medial thickening after vascular injury, but still inhibits vascular smooth muscle cell proliferation and increases uterine weight. The partial retention of estrogen responsiveness in ERalpha,betaKO(CH) mice could be due either to the presence of a novel, unidentified estrogen receptor or to functional expression of an estrogen receptor-alpha splice variant in the parental ERalphaKO(CH) mice. To distinguish between these possibilities, we studied recently generated mice fully null for estrogen receptor alpha (ERalphaKO(Strasbourg) [ERalphaKO(St)]) and examined the effect of estrogen on the response to vascular injury. In the present study, we show that after vascular injury in ovariectomized ERalphaKO(St) mice, estrogen has no detectable effect on any measure of vascular injury, including medial area, proteoglycan deposition, or smooth muscle cell proliferation. These data demonstrate that estrogen receptor-alpha mediates the protective effects of estrogen on the response to vascular injury.
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PMID:Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. 1203 98

Complications of atherosclerosis are the most common cause of death in Western societies. Among the many risk factors identified by epidemiological studies, only elevated levels of lipoproteins containing apolipoprotein (apo) B can drive the development of atherosclerosis in humans and experimental animals even in the absence of other risk factors. However, the mechanisms that lead to atherosclerosis are still poorly understood. We tested the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans. Here we present direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins (LDL) is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wild-type control LDL. We conclude that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.
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PMID:Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. 1206 68

Glycation is responsible for disruption of lipoprotein functions leading to the development of atherosclerosis in diabetes. The effects of apolipoprotein E (apoE) glycation were investigated with respect to its interaction with receptors. The interaction of apoE with the low density lipoprotein receptor (LDL-R) and scavenger receptor A (SR-A) was measured by competition experiments performed using, respectively, on a human fibroblast cell line 125I-LDL, and on a murine macrophage cell line (J774) 125I-acetylated LDL, and unlabeled apoE/phospholipid complexes. Glycated apoE binding to heparin and heparan sulfates (HS) was assessed by surface plasmon resonance (SPR) technology. Site-directed mutagenesis was then performed on Lys-75, the major glycation site of the protein. The prepared mutant protein proved to be useful as a tool to study the role of Lys-75 in apoE glycation. The findings showed that, although glycation has no effect on apoE binding either to the LDL-R or to SR-A, it impairs its binding to immobilized heparin and HS. The glycation of Lys-75 was found to be proceed rapidly and contributed significantly to total protein glycation. We propose that, in the case of diabetes, glycation may lead to the atherogenicity of apoE-containing lipoproteins disturbing their uptake via the HS proteoglycan pathway.
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PMID:Early-glycation of apolipoprotein E: effect on its binding to LDL receptor, scavenger receptor A and heparan sulfates. 1206 54


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