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 synthesis of proteoglycans by aorta explants from rabbits with diet-induced atherosclerosis and controls was studied by 35S-incorporation. Proteoglycans were isolated under dissociative conditions from incubation medium and from arterial explants. Additionally, the tissue proteoglycans that were not extracted by 4 M guanidine-HCl were solubilized by digestion of the tissue by elastase in the presence of proteinase inhibitors. The residual tissue was hydrolyzed by papain and glycosaminoglycans were isolated. The atherosclerotic aorta tissue incorporated twice the amount of 35S into proteoglycans than observed for controls; in both groups about 70% of the label incorporated into the tissue was noted in the proteoglycans extracted by guanidine-HC;, while about 30% of the total 35S-labeled proteoglycans synthesized by the explants were found in the media. Atherosclerotic tissue incorporated 35S predominantly into chondroitin sulfate proteoglycans when compared to control tissue. The chondroitinase ABC-digestable proteoglycans that were extracted by guanidine-HCl from atherosclerotic tissues were of larger molecular size than those from control tissue, but the core proteins from these preparations were similar. The heparan sulfate proteoglycan that was obtained by dissociative extraction from atherosclerotic tissue had greater amounts of N-acetyl and lesser amounts of N-sulfate ester groups than the preparation from control tissue. Digestion of the tissue by elastase yielded heparan sulfate proteoglycan as the major constituent in both groups, although atherosclerotic tissue contained relatively small amounts of this proteoglycan. The residual tissue from both groups contained chondroitin sulfate and heparan sulfate as the major glycosaminoglycans with the latter showing a decrease with atherosclerosis. Atherosclerotic tissue secreted into the medium about two-fold more 35S-labeled proteoglycans with larger molecular size than control tissue; proteoglycans of the heparan sulfate and chondroitin sulfate types were the major constituents in the culture medium of both tissues. Thus, proteoglycans undergo both quantitative and qualitative changes in atherosclerosis, reflecting the enhanced smooth muscle cell activity. These changes are potentially important in modulating lipoprotein binding and hemostatic properties, as well as fibrillogenesis of the arterial wall.
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PMID:Composition of proteoglycans synthesized by rabbit aortic explants in culture and the effect of experimental atherosclerosis. 334 58

Glycosaminoglycans (GAGs) and their fractions were measured in relation to age. The material for examination consisted of labile intervertebral disks (27 cases) obtained during operations for discogenic lumbosacral radiculites and disks obtained from people (n = 35) who had died in accidents. The findings showed marked deviations in the total GAGs and their fractions in labile disks, which differed from age-specific changes. The changes revealed in animals with cholesterol atherosclerosis (50 rabbits) and chronic papain degeneration (56 rabbits) resembled those characteristic of vertebral osteochondrosis. It is concluded that degenerative dystrophic changes in osteochondrosis may be induced by both atherosclerotic process and an elevated activity of lysosome enzymes.
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PMID:[Role of glycosaminoglycans in the pathogenesis of vertebral osteochondrosis (clinico-experimental study)]. 376 93

The interaction of glycosaminoglycans and proteoglycans with low density lipoproteins has been studied. Aortic and cartilaginous glycosaminoglycans are retained in LDL affinity columns and produce turbidity when added to LDL in presence of Ca2+. When extracted from whole aortic walls, dermatan sulfate is the glycosaminoglycan that shows greatest affinity for LDL. However, when using the glycosaminoglycans obtained by papain hydrolysis of the proteoglycans extracted from aorta, the binding affinity with LDL was similar for dermatan sulfate and chondroitin 4/6-sulfate. Removal of the protein core of the aortic or cartilaginous proteoglycans did not prevent interaction with LDL. However, treatment with testicular hyaluronidase abolished totally such interaction. When aortic glycosaminoglycans and proteoglycans were applied to LDL affinity columns in presence of Ca2+, a marked increase in the average molecular weight of the glycans found in the eluates of higher NaCl concentration was observed. This result suggests that the molecular weight of the glycosaminoglycans is a relevant factor for the binding of these compounds to LDL.
Atherosclerosis 1984 Feb
PMID:The binding of human aortic glycosaminoglycans and proteoglycans to plasma low density lipoproteins. 671 67

A genetically selected line of White Carneau pigeons (WC-2) was studied in an attempt to relate changes in composition and content of aortic glycosaminoglycan (GAG) to increased atherosclerosis susceptibility. The WC-2 pigeons were fed an atherogenic diet for 3 months and, when compared to randomly bred White Carneau (RBWC) controls, they showed similar plasma cholesterol concentrations but significantly greater aortic atherosclerosis. In the WC-2 pigeons, 35% of the aortic surface was covered with plaque compared with only 12% in RBWC pigeons; WC-2 birds showed cholesterol contents of 3.3 mg/aorta/500 g body weight, while the RBWC birds had only 0.9 mg/aorta/500 g body weight. After papain treatment of delipidated dried artery, the aortic GAG were isolated, purified using cetylpyridinium chloride, and identified and quantitated by a combination of procedure including selective enzymatic digestion and electrophoresis. In both pigeon groups, aortic GAG included 8% hyaluronic acid, 11% dermatan sulfate, 15% heparan sulfate, and 66% chondroitin sulfate. For the entire group, total aortic GAG content was 35% greater in WC-2 pigeons. Since we did not know if this increase in GAG was simply due to increased atherosclerosis in the WC-2 birds, we sorted the pigeons into matched groups representing minimal, moderate, and severe atherosclerosis on the basis of aortic cholesterol content. At all levels of cholesterol, all GAG contents were greater in the aortas of WC-2 pigeons. The accumulation of dermatan sulfate was 30% higher than in RBWC birds in the minimal arteriosclerosis group, 101% higher in the moderate group, and 53% higher in the severe group. Hyaluronic acid tended to decrease as aortic cholesterol contents increased in WC-2 pigeons. Reduced hyaluronic acid and increase dermatan sulfate may suggest the presence of an altered hyaluronic acid-dermatan sulfate-containing proteoglycan aggregate in the intercellular matrix of the WC-2 pigeon aorta. Possible consequences include increased artery permeability and a binding and retention of lipoproteins in the artery wall. These factors may explain why atherosclerosis develops at an increased rate in the WC-2 pigeon.
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PMID:Aortic glycosaminoglycans in genetically selected WC-2 pigeons with increased atherosclerosis susceptibility. 729 92

The effects of the low-molecular-weight fraction of papain-hydrolyzed pork meat (LMF) on the plasma cholesterol level and the generation of atherosclerosis were studied in rabbits fed a cholesterol-enriched diet. In LMF-fed rabbits, the plasma and liver cholesterol concentrations were both significantly lower (p<0.0 1) than in rabbits fed untreated pork meat (PM). Similarly, the cholesterol concentrations of the chylomicron and VLDL fractions were significantly lower in LMF-fed rabbits than in rabbits fed PM. Deposition of lipid in transverse sections of the aortic arch was significantly less in rabbits fed LMF than in those fed PM. Electron microscopic studies revealed preventive effects against premature atherosclerotic lesions in the aorta of rabbits fed LME These results indicate that LMF has a hypocholesterolemic action and preventive effects against premature atherosclerosis.
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PMID:Papain-hydrolyzed pork meat reduces serum cholesterol level and premature atherosclerosis in dietary-induced hypercholesterolemic rabbits. 1118 55

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

Atherosclerosis is characterized by a thickening and loss of elasticity of the arterial wall. Loss of elasticity has been attributed to the degradation of the arterial elastin matrix. Cathepsins K and S are papain-like cysteine proteases with known elastolytic activities, and both enzymes have been identified in macrophages present in plaque areas of diseased blood vessels. Here we demonstrate that macrophages express a third elastolytic cysteine protease, cathepsin V, which exhibits the most potent elastase activity yet described among human proteases and that cathepsin V is present in atherosclerotic plaque specimens. Approximately 60% of the total elastolytic activity of macrophages can be attributed to cysteine proteases with cathepsins V, K, and S contributing equally. From this 60%, two-thirds occur extracellularly and one-third intracellularly with the latter credited to cathepsin V. Ubiquitously expressed glycosaminoglycans (GAGs) such as chondroitin sulfate specifically inhibit the elastolytic activities of cathepsins V and K via the formation of specific cathepsin-GAG complexes. In contrast, cathepsin S, which does not form complexes with chondroitin sulfate is not inhibited; thus suggesting a specific regulation of elastolytic activities of cathepsins by GAGs. Because the GAG content is reduced in atherosclerotic plaques, an increase of cathepsins V and K activities may accelerate the destruction of the elastin matrix in diseased arteries.
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PMID:Cathepsin V, a novel and potent elastolytic activity expressed in activated macrophages. 1519 1

Cathepsin S is a cysteine protease in the papain super-family. Studies have shown that it is highly expressed in antigen-presenting cells. Along with other lysosomal proteases, cathepsin S plays an important role in the major histocompatibility complex class II-restricted antigen presentation, especially in the degradation of the invariant chain, a chaperone peptide bound to the class II complex. Compared with other lysosomal cysteine proteases, cathepsin S has displayed some unique characteristics. As a result, cathepsin S has been implicated as a potential target in the treatment of various disorders ranging from autoimmune diseases to atherosclerosis. Furthermore, a number of small-molecule cathepsin S inhibitors have demonstrated efficacy in disease-relevant models.
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PMID:Cysteine protease cathepsin S as a key step in antigen presentation. 1533 87

The accumulation of extracellular matrix components such as proteoglycans is a hallmark of an atherosclerotic lesion. A large heparan sulfate proteoglycan, perlecan, dramatically increases in the advanced lesion, and vascular smooth muscle cells are the cell type responsible for the accumulation. In this study, we investigated the effects of thrombin on the proteoglycan synthesis in cultured human coronary smooth muscle cells to determine the interrelationship between the accumulation of proteoglycans and the procoagulant state of blood in atherosclerosis. The cells were metabolically labeled with [(35)S]sulfate or (35)S-labeled amino acids in the presence of thrombin, and the labeled proteoglycans were characterized by Sepharose CL-4B molecular sieve chromatography and DEAE-Sephacel ion-exchange chromatography. The glycosaminoglycan M(r) and composition were analyzed by Sepharose CL-6B chromatography, and the core protein M(r) was determined by SDS-polyacrylamide gel electrophoresis before and after digestion with chondroitinase ABC or papain. The results indicate that thrombin increases the cell layer-associated heparan sulfate proteoglycan with a core protein size of approximately 400 kDa without any change in the length of the glycosaminoglycan chains when the cell density is high. The heparan sulfate proteoglycan was identified as perlecan by Western blot analysis. In addition, quantitative reverse transcription-polymerase chain reaction showed that thrombin elevated the steady-state level of perlecan mRNA but not that of versican, decorin, and syndecan-1 mRNAs, although that of biglycan mRNA was moderately elevated. Furthermore, the percentage of disaccharide units that compose perlecan heparan sulfate chains remained unaffected by thrombin. Therefore, it is suggested that thrombin induces the perlecan core protein synthesis without influencing the formation of the heparan sulfate chains in human coronary smooth muscle cells at a high cell density. The regulation of proteoglycan synthesis by thrombin may be involved in the accumulation of perlecan in advanced lesions of atherosclerosis.
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PMID:Induction of synthesis of a large heparan sulfate proteoglycan, perlecan, by thrombin in cultured human coronary smooth muscle cells. 1571 25

Endogenous cysteine proteases were given much attention lately, as their role in a variety of pathophysiological disorders became evident. Amongst them cathepsins, which are thought to be implicated in mediation of osteoporosis, cancer progression, atherosclerosis, and many other conditions, are of considerable interest as drug targets. In the presented work, papain was chosen as a model cysteine protease and panning protocol was optimized for selection of papain-binding phage-displayed peptides from a commercially available combinatorial peptide library. Different selection strategies were applied in order to select high-affinity binders. Ultimately, five cyclic peptides (CNWAAGYNCGGGS-NH2, CWSMMGFQCGGGS-NH2, CWEWGGWHCGGSS-OH, CNWTLGGYKCGGGS-NH2 (all cyclized through formation of intramolecular disulphide bond), and GNWTLGGYKGG (cyclized head-to-tail)) were synthesized and tested for inhibitory activity towards papain and human cathepsins L, B, H, and K. The peptides possess inhibitory constants in the low micromolar to mid-nanomolar range and exhibit certain selectivity for different lysosomal cysteine proteases included in this study.
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PMID:Affinity selection to papain yields potent peptide inhibitors of cathepsins L, B, H, and K. 1591 50


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