Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.6.4 (chondroitinase)
 2,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heparin significantly increased the amount of newly synthesized apolipoprotein E (apoE) released by HepG2 cells. Culturing cells in the presence of 10 micrograms/ml of heparin for 2-6 days caused a 1.3-fold (day 2) to 3-fold (day 6) increase of extracellular apoE without affecting the total amount of apoE synthesized by the cells. The amounts of apoA-I and apoB produced by HepG2 cells were unaffected by heparin. Surprisingly, short-term treatment with heparin (15-30 min) also increased extracellular apoE by 2- to 3-fold. In this situation, heparin exerted its effect on apoE post-translationally. Among glycosaminoglycans (GAGs), only heparan sulfate mimicked heparin at a concentration of 10 micrograms/ml; hyaluronic acid and the chondroitin sulfates were effective only at a higher concentration (100 micrograms/ml). Extracellular apoE was not increased by treating cells with anti-apoE antiserum or a heparin-binding peptide of apoE (amino acids 130-169). Removal of cell surface-associated GAGs by culturing cells in 4-methylumbelliferyl-beta-D-xyloside ablated the effect of heparin on apoE. ApoE was released from cells by treatment with heparinases I and III, but not by chondroitinase ABC. The results provide evidence that a heparin-releasable pool of newly synthesized apoE is associated with cell surface GAGs that resemble heparin and/or heparan sulfate.
 ...
PMID:Heparin releases newly synthesized cell surface-associated apolipoprotein E from HepG2 cells. 838 53

Pigeon and rabbit beta-migrating very low density lipoprotein (beta-VLDL) are similar in size and composition, yet rabbit beta-VLDL consistently stimulates greater cholesteryl ester accumulation in pigeon peritoneal macrophages than does pigeon beta-VLDL. The purpose of this study was to determine the mechanism of this difference. Pigeon beta-VLDL bound to both a high and low affinity site while rabbit beta-VLDL bound primarily to a low affinity site. The high affinity site had the characteristics of the LDL receptor. Most rabbit beta-VLDL and some pigeon beta-VLDL bound to the low affinity site that was not down-regulated by cholesterol loading. beta-VLDL binding to the low affinity site and subsequent internalization and degradation were mediated by cell surface heparan sulfate proteoglycans (HSPG). Evidence for this includes inhibition of binding and uptake by chlorate, which prevents sulfation of proteoglycans, and by treatment with heparinase but not chondroitinase ABC. beta-VLDL uptake was stimulated by lipoprotein lipase (LpL) and apolipoprotein E (apoE), both known to bind HSPGs. Uptake and degradation of beta-VLDL were not mediated by the LDL receptor or the alpha(2)MR/LRP. Thus, binding of beta-VLDL to low affinity, high capacity HSPG binding sites on pigeon macrophages appears to directly promote internalization and degradation and is largely responsible for the greater ability of rabbit beta-VLDL to stimulate cholesterol accumulation.
 ...
PMID:Heparan sulfate proteoglycans mediate internalization and degradation of beta-VLDL and promote cholesterol accumulation by pigeon macrophages. 914 91

Aggregated low-density lipoprotein (LDL) was shown to be present in the atherosclerotic lesion, but the mechanism responsible for its formation in vivo is not known yet. To find out whether LDL aggregation occurs in the arterial wall during atherogenesis, LDLs were extracted from the aortas of apolipoprotein E-deficient (E(0)) mice during their aging (and the development of atherosclerosis), and were analyzed for their aggregation states, in comparison to LDLs isolated from aortas of control mice. LDL isolated from aortas of E(0) mice was already aggregated at 1 month of age and its aggregation state substantially increased with age, with 3-fold elevation at 6 months of age compared to younger, 1-month-old, mice. Only minimal aggregation could be detected in LDL derived from control mice. Electron microscopy examination revealed that LDL particles from aortas of the E(0) mice were heterogeneous in their size, ranging between 20 and 300 nm. The mouse aortic LDL contained proteoglycans (PGs) and their content increased with the age of the mice, with about 2-fold higher levels than those found in LDLs derived from aortas of control mice. Macrophage-released PGs were previously demonstrated to enhance LDL aggregation in vitro. However, their involvement in LDL aggregation in vivo has not been studied yet. Thus, we next studied the effect of arterial macrophage-released PGs on the susceptibility of plasma LDL to aggregation by Bacillus cereus sphingomyelinase (SMase). Foam cell macrophages were isolated from aortas of the atherosclerotic E(0) mice at 6 months of age and were found to be loaded with cholesterol and to contain oxidized lipids. To analyze the effect of macrophage-released PGs on LDL aggregation, PGs were prelabeled by cell incubation with [35S]sulfate, followed by incubation of macrophage-released PGs with E(0) mouse plasma LDL (200 microg protein/ml) for 1 h at 37 degrees C. [35S]Sulfated PGs were found to be LDL-associated and the susceptibility of PG-associated LDL to aggregation by SMase was increased by up to 45% in comparison to control LDL. Similar results demonstrating the involvement of PGs in LDL aggregation were obtained upon incubation of LDL with increasing concentrations of PGs that were isolated from the entire aorta of E(o) mice (rather than the isolated macrophages). The stimulatory effect of macrophage-released PGs on LDL aggregation was markedly reduced when the PGs were pretreated with the glycosaminoglycan-hydrolyzing enzymes, chondroitinase ABC or chondroitinase AC, and to a much lesser extent with heparinase. We thus conclude that macrophage-released chondroitin sulfate PG can contribute to the formation of atherogenic aggregated LDL in the arterial wall.
 ...
PMID:Macrophage-released proteoglycans enhance LDL aggregation: studies in aorta from apolipoprotein E-deficient mice. 1078 39

Proteoglycans (PGs) have been suggested to work as receptors in lipoprotein uptake mechanisms. An interaction between apolipoprotein E (apoE) and glucosaminoglycans (GAG), polysaccharides linked to proteoglycans, has been proposed in this pathway. At the same time, proteoglycans, apoE as well as lipoprotein receptors have been reported to be constituents of amyloid plaques, one hallmark of Alzheimer's disease. With this study, we are the first to investigate the interaction between beta very low density lipoprotein (beta-VLDL) and a neuronal highly abundant GAG, chondroitin sulphate (CS), comparing hippocampal neurons, expressing high levels of low density lipoprotein receptor related protein (LRP) and U373 astrocytoma cells, highly positive for the low density lipoprotein receptor (LDLR). We were able demonstrate that degradation of chondroitin sulphate proteoglycans (CSPGs) with chondroitinase ABC resulted in reduced (125)I-beta-VLDL uptake. We showed that externally added CSs compete with internalization of beta-VLDL. The effect was found to be dose-dependent, but was influenced neither by cell type, nor receptor type. The position of sulphation of added CSs showed only a slight influence. The data generated suggested an interaction between apolipoproteins and soluble CSs; therefore, 3H-cholesterol linked to apoE was coadministered with CSs to the cells. The results revealed that apoE bound, but no unbound cholesterol, was reduced in cellular internalization, suggesting that CSPGs may be involved in lipoprotein uptake in the intact brain, mediated, at least in part, by apoE.
 ...
PMID:Role of chondroitin sulphate in the uptake of beta-VLDL by brain cells. 1619 Aug 94