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)

There is abundant evidence that changes in diet and various types of vessel wall injury can independently induce the growth of arterial lesions in experimental animals. These lesions closely resemble those found in humans with atherosclerosis. Whether endothelial injury or accumulation of lipoprotein in the arterial intima is the initial event, the progression of the disease is characterized by changes in the neointima that favor the deposition of lipid. The metabolism of proteoglycans may be especially important in this process; this is relevant to diabetes because changes in proteoglycan metabolism are associated with this disease. Insulin and growth hormone may favor the proliferation of smooth muscle cells in the arteries of diabetic patients. Many agents, which are potentially injurious to the endothelium, accentuate the response of the vessel wall to injury. Modifications of the thrombotic process, such as increased production of thromboxane by platelets, decreased production of prostacyclin by the endothelium, and increased production of von Willebrand factor further enhance the thrombotic process and may be important in the initiation and subsequent progression of atherosclerosis in diabetics. Alterations in lipoprotein metabolism may also facilitate the development of endothelial injury.
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PMID:Pathogenesis of atherosclerosis. 390 56

The aortic wall of the human ascending aorta from 44 patients operated on for annulo-aortic ectasia (AAE) was studied. Light microscopy revealed significantly greater cystic change, elastic fragmentation, fibrosis and disappearance of smooth muscle cells in aortic media in AAE than in control specimens taken at autopsy. Occasional aortae, however, were morphologically almost normal. Eight of the patients had Marfan's syndrome. No significant differences were observed between them and the other 36 patients, except for a tendency to have less pronounced fibrosis. There were 9 patients who, in addition to the changes mentioned, had advanced atherosclerosis, and their aortae showed more extensive fibrosis and medial necrosis. Pooling of proteoglycan matrix, degeneration of elastic lamellae, increased amount of collagen and necrosis of smooth muscle cells characterized the electron microscopic findings of 13 patients. The collagen fibers seemed to be of normal shape. In conclusion, changes in annulo-aortic ectasia are characterized by severe cystic medial necrosis. The changes are basically similar in Marfan and non-Marfan patients.
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PMID:Annulo-aortic ectasia. Light and electron microscopic changes in aortic media. 392 61

Arterial dermatan sulfate proteoglycans (DS-PG) were isolated from randomly bred White Carneau (RBWC) pigeons and a line of White Carneau pigeons (WC-2) genetically selected for increased atherosclerosis susceptibility. To characterize the basic proteoglycan (PG) structure and to identify structural differences that may relate to a specific arterial phenotype, embryos were labeled with radioactive sulfate in ovo and PG were isolated from aortas with 4.0 M GdnHCl. DS-PG were separated from chondroitin sulfate PG by gel chromatography and further purified by CsCl buoyant density ultracentrifugation and ion-exchange of chromatography. The DS-PG monomers from the two genetic lines of pigeons eluted at different positions on two high pressure liquid chromatography (HPLC) gel permeation systems, which suggested a structural difference between the two monomers. Analysis of the monomer components showed a similar protein core molecular weight of 50,000 for each and a similar amino acid composition. Glycosaminoglycans (GAG) molecular weights were estimated to be 15,000 for WC-2 and 18,000 for RBWC. The findings suggest a basic difference in post-translational processing of PG in the two pigeon types which may reflect distinct functional properties associated with resistance or susceptibility to atherosclerosis.
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PMID:Arterial dermatan sulfate proteoglycan structure in pigeons susceptible to atherosclerosis. 396 3

The interaction of low density lipoproteins (LDL) with chondroitin sulfate-rich arterial proteoglycans appears to be initiated by coulombic interactions that lead to insoluble complexes. Once formed, large LDL aggregates are held together by non-polar associations. The irreversible formation of LDL proteoglycans aggregates was evaluated for different LDL preparations by definition of an avidity coefficient (Ar) using a Langmuir isotherm. LDL from different subjects, when tested against the same lipoprotein-complexing proteoglycan (LCP), gave Ar values ranging from 1-9 X 10(6) L/M. High avidity values were associated to lipoproteins with apparent isoelectric points above 6.5. These lipoproteins show low sialic acids content. The content of N-acetyl and N-acetyl,O-acetyl sialic acid was found inversely correlated with the avidity coefficient for the arterial LCP. Reductions of 42% on the LDL sialic acid content, by neuraminidase treatment, induced a 10-fold increment in their avidity for the lipoprotein complexing proteoglycan. The results indicate that at low ionic strength and physiological Ca2+-concentration and pH, the surface charge of LDL is an important modulator of the interaction with the arterial proteoglycan. Sialic acid, perhaps because of its exposure at the LDL surface, plays a determinant role in the in vitro association of LDL with the polyanionic proteoglycans. It is possible that in the intima-media the sialic residues of LDL and its balance of surface charges will control part of the interactions with the proteoglycans of the extracellular matrix.
Atherosclerosis 1985 Apr
PMID:Interaction of low density lipoproteins with arterial proteoglycans. The role of charge and sialic acid content. 400 85

We studied the effect of complexes of low-density lipoproteins (LDL) and different proteoglycan preparations from bovine aorta on LDL degradation and cholesteryl ester accumulation in mouse peritoneal macrophages. Native proteoglycan aggregate containing proteoglycan monomers, hyaluronic acid and link protein was isolated by associative extraction of aortic tissue, while proteoglycan monomer was obtained by dissociative isopycnic centrifugation of the native proteoglycan aggregate. In vitro proteoglycan aggregates were prepared by reaction of the proteoglycan monomer with exogenous hyaluronic acid. 125I-labeled LDL-proteoglycan complexes were formed in the presence of 30 mM Ca2+ and incubated with macrophages. At equivalent uronic acid levels in the proteoglycans the degradation of 125I-labeled LDL contained in the native proteoglycan aggregate complex was 3.7-7.5-fold greater than the degradation of the lipoprotein in the proteoglycan monomer complex. Degradation of 125I-LDL in the in vitro aggregate complex, while higher than that in the monomer complex, was markedly less than that in the native aggregate complex. The larger size and the greater complex-forming ability of the native proteoglycan aggregate might account for the greater capacity of the aggregate to promote LDL degradation in macrophages. The proteoglycan-stimulated degradation of LDL produced a marked increase in cholesteryl ester synthesis and content in macrophages. The LDL-proteoglycan complex was degraded with saturation kinetics, suggesting that these complexes are internalized through high-affinity receptors. Degradation was inhibited by the lysosomotropic agent, chloroquine. Acetyl-LDL, but not native LDL, competitively inhibited the degradation of the 125I-LDL component of the complex. Polyanionic compounds such as polyinosinic acid and fucoidin, while completely blocking the acetyl-LDL-stimulated cholesteryl ester formation, had no effect on the proteoglycan aggregate-stimulated cholesterol esterification. This suggests that LDL-proteoglycan complex and acetyl-LDL are not entering the cells through the same receptor pathway. These results demonstrate that the interaction of LDL with arterial wall proteoglycan aggregates results in marked cholesteryl ester accumulation in macrophages, a process likely to favor foam cell formation. A role for arterial proteoglycans in atherosclerosis is obvious.
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PMID:Complexes of low-density lipoproteins and arterial proteoglycan aggregates promote cholesteryl ester accumulation in mouse macrophages. 406 79

Proteoglycans and glycosaminoglycans of the intima-media extracellular matrix have been stated to play a role in lipoprotein deposition associated with atherogenesis. It is therefore important to characterize the active lipoprotein-complexing moiety of these macromolecular aggregates. We have isolated a soluble proteoglycan aggregate of approximately 5 X 10(6) molecular weight after homogenization of human aortic intima-media in an isosmotic sucrose solution, sequential differential centrifugation, dialysis, exclusion chromatography and preparative electrophoresis. This proteoglycan aggregate, labelled lipoprotein-complexing proteoglycan (LCP), has been previously shown to form specific complexes with low density lipoproteins, either isolated or in sera. Density gradient centrifugation in dissociative conditions of the LCP, cellulose acetate acetate electrophoresis of the subfractions, chondroitinases treatment and high performance liquid chromatography of the unsaturated disaccharides indicated that the glycosaminoglycan moiety was composed of 56% chondroitin-6-SO4, 26% hyaluronate and/or undersulfated chondroitin and 17% chondroitin-4-SO4. In pore-gradient polyacrylamide gel electrophoresis, the hyaluronate monomer appeared to have a molecular weight of 250000 while that of the chondroitin sulfates ranged between 50000 and 70000 after extensive treatment with protease. The fractions enriched in the chondroitin sulfate monomers were the most reactive towards LDL and their reactivity was abolished by chondroitinase AC indicating that the lipoprotein-complexing capacity of the LCP aggregate is associated to these molecules.
Atherosclerosis 1983 Dec
PMID:Partial structure of the active moiety of a lipoprotein complexing proteoglycan from human aorta. 666 Dec 68

Arterial smooth muscle cells cultured from normotensive and hypertensive rats incorporated [35S]sulfate into the extracellular and pericellular sulfated proteoglycans and endocytose extracellular [35S]proteoglycans at a significantly higher rate in the phase of logarithmic growth than did nondividing cells. 35S incorporation into proteoglycans was positively correlated with [3H]thymidine incorporation into the cellular TCA-precipitable material. The rates of [35S]proteoglycan synthesis and endocytosis per cell pr day were higher in smooth muscle cells from hypertensive than from normotensive animals, the observed differences being related to a higher average protein content of smooth muscle cells cultured from hypertensive rats as compared with cells of normotensive animals. Gel filtration under dissociative conditions separated the [35S]proteoglycans into high and low molecular weight fractions (A, B) differing in glycosaminoglycan composition and their ability to be endocytosed by smooth muscle cells. The relative proportion of the high molecular weight proteoglycan fraction A decreased continuously from sparse to confluent cell cultures.
Atherosclerosis 1982 Dec
PMID:[35S]proteoglycan metabolism of arterial smooth muscle cells cultured from normotensive and hypertensive rats. 715 1

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 preparation of a proteoglycan (PG) from human aortic intima-media is described. The PG was obtained from intima-media homogenates by differential centrifugation, exclusion chromatography and preparative agarose electrophoresis. Crude or purified preparations of the proteoglycan are capable of forming specific insoluble complexes with LDL, purified or in serum. This product has been labelled lipoprotein-complexing proteoglycan (LCP-3). On agarose and cellulose acetate electrophoresis LCP-3 appears as a single band. However, its glycosaminoglycan (GAG) moiety shows a composition and chromatographic behaviour compatible with hybrid or mixed chains of chondroitin-6-so4, dermatan sulfate and heparin and/or heparan sulfate. The specificity of LCP-3 for LDL disappears when it is treated with testicular hyaluronidase or proteolytic enzymes. Ionic strength, pH, Ca++ and Mg++ modulate the amount of LDL insolubilized. The amino acid composition of the protein from LCP-3 is that of a basic protein(s), perhaps bound covalently through xylose--serine residues to the GAG's. The estimated molecular weight of LCP-3 is 1 to 5 x 10(6) daltons. The presence of LCP-3 to intima-media and its specificity for interacting with LDL at conditions near to physiological ones are suggestive of the role that this type of structure may play in the association of the atherogenic lipoproteins with components of the arterial intima-media.
Atherosclerosis 1980 Mar
PMID:Characterization and properties of a lipoprotein-complexing proteoglycan from human aorta. 736 2

Through immunohistochemical studies we have identified the cell-surface proteoglycan, NG2, on blood vessels throughout the rat embryo. The particular cell type expressing this chondroitin sulfate proteoglycan, however, is dependent upon tissue location. Microvessels within the rat CNS express NG2 on endothelial cells, while in blood vessels outside the CNS, NG2 is found on smooth muscle cells. To analyze what role NG2 might play in these blood vessels, an enzymatic dissociation protocol was used to establish primary cultures of vascular smooth muscle cells from Postnatal Day 3 rat aorta. In this study we demonstrate the involvement of NG2 in the mitogenic and chemoattractant responses of smooth muscle cells to PDGF. In assays measuring either DNA synthesis or cell migration, treatment of smooth muscle cells with anti-NG2 immunoglobulins decreased their responses to PDGF-AA but had no effect upon their ability to react to PDGF-BB. These results support a role for NG2 in potentiating signaling through the alpha PDGF receptor in vascular smooth muscle cells. The presence of the proteoglycan on a large subpopulation of these cells could provide an enhanced response to the growth factor in times of active normal growth or in pathological conditions, such as arterial injury or atherosclerosis.
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PMID:Participation of the NG2 proteoglycan in rat aortic smooth muscle cell responses to platelet-derived growth factor. 758 50


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