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)

Aortic glycosaminoglycans were separated into fractions of increasing molecular weights containing heparan sulfate or chondroitin 4/6-sulfate + dermatan sulfate. When these fractions were added to plasma low density lipoproteins (LDL) in the presence of Ca2+, only chondroitin 4/6 sulfate + dermatan sulfate of high relative molecular weight produced turbidity. Treatment with testicular hyaluronidase abolished totally the formation of insoluble complex. When these glycosaminoglycans were applied to LDL-affinity columns in the presence of Ca2+, higher NaCl concentrations were necessary for the elution of the high relative molecular weight chondroitin sulfate. Heparan sulfate fractions did not produce turbidity when added to LDL solutions and were eluted from LDL-affinity columns at low NaCl concentrations. All these results suggest that besides the structure (or charge density), the molecular weight of the chondroitin sulfate chains is a relevant factor for the binding of this compound to LDL.
Atherosclerosis 1988 Oct
PMID:Interaction of high molecular weight chondroitin sulfate from human aorta with plasma low density lipoproteins. 314 91

Nine heterozygous patients with familial hypercholesterolemia (FH) were treated by low density lipoprotein (LDL)-apheresis using dextran sulfate cellulose columns. After more than 3 procedures of LDL-apheresis without drug therapy, combination therapy with LDL-apheresis and CS-514 (eptastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase, at a dose of 10 mg twice daily was started. Pre- and post-apheresis serum cholesterol levels were decreased significantly by CS-514, from 289 +/- 24 mg/dl (mean +/- SEM) to 247 +/- 25 mg/dl and from 118 +/- 7 mg/dl to 106 +/- 9 mg/dl, respectively. Pre- and post-apheresis apolipoprotein B levels decreased significantly on CS-514 from 160 +/- 9 mg/dl to 138 +/- 8 mg/dl and from 58 +/- 6 mg/dl to 45 +/- 6 mg/dl, respectively. No adverse effects were observed during the combination therapy. Thus, the addition of an inhibitor of HMG-CoA reductase to LDL-apheresis is a useful method for further reducing serum cholesterol and apolipoprotein B levels in FH heterozygotes.
Atherosclerosis 1988 Aug
PMID:Effects of CS-514 (eptastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on serum lipid and apolipoprotein levels in heterozygous familial hypercholesterolemic patients treated by low density lipoprotein (LDL)-apheresis. 314 45

We investigated lipoprotein metabolism in 14 patients with recessive X-linked ichthyosis (RXLI), a metabolic disease characterized by scaly skin, corneal opacity and steroid sulfatase deficiency. Plasma total cholesterol (TC) levels ranged from normal to slightly low (mean +/- SD: 156 +/- 28 mg/dl). Four patients showed a mild or moderate elevation of plasma triglyceride (TG) levels ranging from 150 to 365 mg/dl. The apoprotein B (apo B) to TC ratio was higher than in normal controls (0.63 +/- 0.11 vs. 0.52 +/- 0.07, P less than 0.01), while plasma apoB levels were within the normal range (99 +/- 17 mg/dl). Polyacrylamide gel electrophoretic mobility of low-density lipoprotein (LDL) was markedly increased in all patients, and further analyses showed that this finding was not due to a change in the particle size of the LDL but to an increased content of cholesterol sulfate (1.0-2.3% of the LDL-cholesterol content). In addition to the alteration of electrophoretic mobility, marked changes in the lipid and apoprotein compositions of the LDL fraction were observed; cholesterol ester content in LDL (LDL-CE) was significantly lower than that of control subjects (37 +/- 4% vs. 41 +/- 2% of total lipids, P less than 0.01), while the triglyceride content (LDL-TG) and apo B to cholesterol ratios in LDL were significantly higher than those of controls (18 +/- 7 vs. 10 +/- 2, P less than 0.001; 1.21 +/- 0.19 vs. 0.73 +/- 0.05, P less than 0.001, respectively). This anionized LDL, in which cholesterol sulfate was increased, was shown to bind to the LDL receptor of fibroblasts to much the same extent as normal LDL. In conclusion, the increase in cholesterol sulfate in LDL fraction not only alters the electrophoretic moiety but also the relative contents of apoB, cholesterol, and triglyceride in the lipoprotein. It does not change the affinity of LDL for the LDL receptor.
Atherosclerosis 1988 Mar
PMID:Characterization of low-density lipoproteins from patients with recessive X-linked ichthyosis. 316 81

Although the selective interaction of low density lipoproteins (LDL) with arterial proteoglycans is known, information is lacking on LDL-binding affinity of different subspecies occurring within a proteoglycan family. Isomeric chondroitin sulfate proteoglycan preparations sedimenting at densities of 1.54 g/ml (D1), 1.50 g/ml (D2) and 1.46 g/ml (D3) were isolated from bovine aorta intima-media under dissociative conditions and subjected to equilibrium binding to LDL-agarose gel. D1, D2 and D3 contained 36%, 37% and 11% dermatan sulfate, respectively. Sulfate to hexosamine ratio was low (0.73) in D1 when compared to D2 and D3 (0.94 and 1.04). Of the total proteoglycans contained in D1, D2 and D3, 41%, 52% and 66% interacted with LDL, respectively. LDL-bound proteoglycans dissociated over a wide range of ionic strengths (0.15-1.0); in comparison, LDL-bound heparin dissociated within a narrow range (0.5-0.75). Unlike other preparations, 30% of bound D3 dissociated at an ionic strength of 1.0. In D1 and D2 the proportion of dermatan sulfate increased in proteoglycan fractions that were bound firmly to LDL, whereas a high affinity fraction in D3 contained no dermatan sulfate. Thus, isomeric chondroitin sulfate proteoglycans display considerable divergence with respect to LDL binding. This may depend not only on the degree of sulfation but on other characteristics of the chondroitin sulfate isomers as well.
Atherosclerosis 1988 Jul
PMID:Low density lipoprotein binding affinity of arterial wall isomeric chondroitin sulfate proteoglycans. 321 55

We examined the glycosaminoglycan (GAG) components in human pulmonary arteries compared to those in the aorta. Definite changes in GAG contents and components were found between the pulmonary arteries and the aorta. The GAG content of the aorta was constantly higher than that of the pulmonary artery. As to the components of the arterial GAGs, however, hyaluronic acid comprised significantly higher proportions of total GAGs in the pulmonary arteries than in the aorta, whereas dermatan sulfate showed lower proportions in the pulmonary arteries than in the aorta. These significant differences are possibly due to either the effect of the continuously different blood pressure on the wall of these two types of arterial vessels or to constitutional changes of their fundamental structures associated with atherosclerosis.
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PMID:High hyaluronic acid and low dermatan sulfate contents in human pulmonary arteries compared to in the aorta. 333 1

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

Myo-intimal proteoglycan metabolism is thought to be important in blood vessel homeostasis, blood clotting, atherogenesis, and atherosclerosis. Human platelet-derived transforming growth factor type beta (TGF-beta) specifically stimulated synthesis of at least two types of chondroitin sulfate proteoglycans in nonproliferating human adult arterial smooth muscle cells in culture. Stimulation of smooth muscle cell proteoglycan synthesis by smooth muscle cell growth promoters (epidermal growth factor, platelet-derived growth factor, and heparin-binding growth factors) was less than 20% of that elicited by TGF-beta. TGF-beta neither significantly stimulated proliferation of quiescent smooth muscle cells nor inhibited proliferating cells. The extent of TGF-beta stimulation of smooth muscle cell proteoglycan synthesis was similar in both nonproliferating and growth-stimulated cells. TGF-beta, which is a reversible inhibitor of endothelial cell proliferation, had no comparable effect on endothelial cell proteoglycan synthesis. These results are consistent with the hypothesis that TGF-beta is a cell-type-specific regulator of proteoglycan synthesis in human blood vessels and may contribute to the myo-intimal accumulation of proteoglycan in atherosclerotic lesions.
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PMID:Transforming growth factor type beta specifically stimulates synthesis of proteoglycan in human adult arterial smooth muscle cells. 347 55

We have examined whether the toxic effects of homocysteine on cultured endothelial cells could result from the formation and action of hydrogen peroxide. In initial experiments with a cell-free system, micromolar amounts of copper were found to catalyze an oxygen-dependent oxidation of homocysteine. The molar ratio of homocysteine oxidized to oxygen consumed was approximately 4.0, which suggests that oxygen was reduced to water. The addition of catalase, however, decreased oxygen consumption by nearly one-half, which suggests that H2O2 was formed during the reaction. Confirming this hypothesis, H2O2 formation was detected using the horseradish peroxidase-dependent oxidation of fluorescent scopoletin. Ceruloplasmin was also found to catalyze oxidation of homocysteine and generation of H2O2 in molar amounts equivalent to copper sulfate. Finally, homocysteine oxidation was catalyzed by normal human serum in a concentration-dependent manner. Using cultured human and bovine endothelial cells, we found that homocysteine plus copper could lyse the cells in a dose-dependent manner, an effect that was completely prevented by catalase. Homocystine plus copper was not toxic to the cells. Specific injury to endothelial cells was seen only after 4 h of incubation with homocysteine plus copper. Confirming the biochemical studies, ceruloplasmin was also found to be equivalent to Cu++ in its ability to cause injury to endothelial cells in the presence of homocysteine. Since elevated levels of homocysteine have been implicated in premature development of atherosclerosis, these findings may be relevant to the mechanism of some types of chronic vascular injury.
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PMID:Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. 351 79

At least two exogenous sources of agents able to control vascular smooth muscle proliferation can be identified. Platelets contain and release mitogens as well as a factor, TGF-beta, that inhibits cell growth on plastic surfaces while stimulating it when cells are grown in suspension in soft agar. Macrophages release mitogens, including PGDF, and macrophage invasion is characteristic of early experimental lesions in fat-fed animals. Finally, it is at least possible that endothelial cell production of mitogens may represent a response to some as yet undefined external injury. The vessel wall also offers sources of growth control endogenous to the smooth muscle cell layers. The vessel wall contains heparan sulfate able to inhibit cell growth of smooth muscle cells, which by themselves can synthesize PDGF. This provides possible positive and negative control of replication intrinsic to the smooth muscle cells themselves. The role of these intrinsic or extrinsic factors in the smooth muscle proliferation of hypertension and atherosclerosis remains hypothetical. It is intriguing to implicate platelets and/or macrophages in the denuding injuries seen in small hypertensive vessels and in advancing atherosclerotic plaques. At least for the latter case, however, there seem to be other critical factors. Simple denudation and thrombosis, for example, are not sufficient to stimulate smooth muscle growth, and the kinetics of proliferation after balloon denudation imply the presence of some other event required to initiate smooth muscle proliferation. Similarly, smooth muscle replication in large vessels of hypertensive animals occurs without loss of endothelial continuity. This implies that replication in response to hypertension depends on factors intrinsic to the vessel wall. Benditt's observation of monoclonality also implies some intrinsic mechanism allowing cells to grow in a focal manner. It is intriguing to consider the possibility that this commitment process could require the release of cells from the intrinsic inhibitory effects of heparan sulfate located around the cells or the synthesis of growth factors secreted by the smooth muscle cells themselves. If we add the hypothesis that only some cells are capable of such a response, we would expect the sort of oligodense phenomenon demonstrated by Benditt. Proof of such a hypothesis, however, will have to await development of methods to explore these mechanisms directly in the vessel wall responding to injury.
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PMID:Common mechanisms of proliferation of smooth muscle in atherosclerosis and hypertension. 354 73

The effect of human arterial proteoglycans (PG1) on the interaction of low density lipoprotein (LDL) with cultured human monocyte-derived macrophages (HMDM) was studied. LDL was insolubilized by treatment with chondroitin-6-sulfate-rich, partially purified PG1. The LDL, resolubilized in culture medium, was added to HMDM. The PG1 pretreated LDL induced lipid accumulation in the HMDM, converting them into foam cells. Mass determination of lipids by spectrophotometric and chromatographic procedures showed a 2-4-fold accumulation of triglycerides, phospholipids, unesterified cholesterol and cholesterol esters in 48 h, in the HMDM incubated with PG pretreated LDL, when compared to those incubated with native LDL. Incorporation of [14C]oleic acid into the HMDM lipid esters correlated with the accumulation. Association of 125I-labeled LDL and of fluorescent labeled LDL (3,3-octadecyl indocarbocyanine) to HMDM also indicated that the PG1-pretreatment of LDL increased its uptake. Density gradient centrifugation, isoelectric focusing and electron microscopy showed that, when added to the cells, the PG1 pretreated LDL was not aggregated or altered in its surface charge. However, controlled trypsin treatment and polypeptide pattern analysis indicate that the accessibility of apoB has been altered. The results suggest that changes in the surface of LDL, induced by the arterial PG1, lead to increased endocytosis of the lipoprotein and stimulation of lipid synthesis in the macrophages. The possibility that a similar process may cause lipid accumulation in arterial macrophages is discussed.
Atherosclerosis 1987 Oct
PMID:Effect of arterial proteoglycans on the interaction of LDL with human monocyte-derived macrophages. 367 9


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