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 types of collagen components extracted from human aortas by repeated pepsin digestion were investigated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE), after differential salt precipitation, cyanogen bromide (CNBr) cleavage and beta-mercaptoethanol reduction. For further extraction of collagen components, repeated pepsin digestion was carried out, and two extracts, the former and latter, were obtained. The greatest increase was seen in type V collagen followed by type III in the former extract. Type I collagen was continually extracted, so the proportion of type I to other types became greater with the number of extractions. SDS-PAGE of the residue treated with CNBr revealed that it contained the greatest amount of type I, followed by the latter extract. Type I collagen comprised approximately two-thirds of the total collagen. It was the most predominant in the intima and adventitia but was also obviously abundant in the media. The proportion of type III collagen to total collagen fell slightly with advancing atherosclerosis, since the amounts of types I and V showed some increase. A band of the alpha 3(V) chain of type V collagen in the intima was occasionally detected between the bands of the alpha 1(V) and alpha 2(V) chains. Basement membrane collagen, type IV, which was extracted predominantly from the intima and subintima, showed a heterogenous distribution as to molecular size, ranging from 50 Kd to 140 Kd. The alpha 1(IV) and alpha 2(IV) collagens were found at positions corresponding to 100 Kd and 80 Kd, respectively. The content of collagen type IV also increased with the proliferative fibrotic process. Type VI collagen was found in the intima and subintima of the human aorta at a position corresponding to an approximate molecular weight of 150 Kd, and it was reduced to fragments of 40 Kd, 45 Kd and 52 Kd.
Atherosclerosis 1986 Jun
PMID:Collagen types in various layers of the human aorta and their changes with the atherosclerotic process. 308 34

Collagenous components were extracted from bovine aorta by pepsin digestion. Differential salt precipitations separated the interstitial from the basement membrane (BM) collagens, and the latter were subsequently separated into three distinct types. Ion exchange chromatography, SDS-slab gel electrophoresis, cyanogen bromide and protease V8 peptide mapping, and amino acid analysis were used to characterize the component chains within each of these types. The major BM-class contained three distinct chains which were identical to the alpha 1(V), alpha 2(V) and alpha 3(V) chains of type V collagen from normal human placenta. The stoichiometry of the chains suggests a [alpha 1(V)]2 alpha 2(V)-helical organization, but the role of the alpha 3(V) chain in the overall structural organization of collagen V remains unknown. The second BM-class contained a heterogeneous group of molecules ranging in size from 40 000 to 140 000 daltons. Two predominant chains within this group were characterized as the alpha 1(IV) and alpha 2(IV) chains of type IV collagen. The last class of BM collagens consisted primarily of high molecular weight components; upon reduction these gave rise to two low molecular weight collagenous species (40 K and 45 K) characteristic of type VI, low molecular weight or 'linker' collagens. The functional roles of the isolated BM collagens, either individually or collectively, has not been ascertained to date.
Atherosclerosis 1984 Jan
PMID:Characterization of basement membrane collagens of bovine aortae. 669 80

This review deals with some structural features of the collagen molecules involved in the adhesion of platelets representing the initial step of hemostasis, thrombosis, and (partly) atherosclerosis. The adhesion occurs at the level of a vascular lesion or deendothelialized area, whatever the genetic type of collagen. In vitro experiments with purified collagens have shown that vascular interstitial collagens (types I and III, the latter present in subendothelium) as well as basement membrane-derived collagens (types IV and V) induce an adhesion of platelets, provided that an ordered arrangement linked to the quaternary and tertiary structures of their molecule is preserved. Whatever the quaternary structure, the important point seems to be the size of the fibers and more precisely the availability of an optimal number of adhesion sites on multimerized fibers. Various direct or indirect proofs (for example, the occurrence of the impairment of collagen multimerization on platelet adhesion/aggregation) are reviewed. Our recent studies on interstitial collagens have shown the involvement of certain specific amino-acid sequences obtained after cyanogen bromide cleavage of collagen. These are the C-terminal alpha1 (I) CB6 peptide of the alpha 1 chains of type I collagen (216 amino acids) and the central alpha1 (III) CB4 peptide from type III collagen (149 amino acids) Cleavage of this last peptide by chymotrypsin, hydroxylamine, and trypsin has suggested the possibility that a nonapeptide (sequence gly-lys-hyp-gly-glu-hyp-gly-pro-lys) is a minimum site of adhesion for platelets. This assumption has been reinforced by the fact that a synthetic nonapeptide with this sequence specifically inhibits the aggregation of platelets to collagen in vitro. The adhesion of platelets may consequently be due to the repetitive staggering of short amino acid sequences (such as this nonapeptide from type III collagen) along the rigid structure formed by a multimerized collagen fiber.
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PMID:[The adhesion of blood platelets to collagen: molecular features of collagen (author's transl)]. 702 81

Estimation of collagens types I and III in pepsin digests and by analysis of specific cyanogen-bromide derived peptides by SDS-polyacrylamide gel electrophoresis, has indicated that both the undiseased human aortic media and the atherosclerotic plaque of the diseased intima contain more type I collagen than type III. There was only a relatively small shift in composition in favour of type I collagen in the diseased compared to the undiseased tissue. Diffusely thickened intima was similar in composition to the atherosclerotic plaque. These results suggest that both atherogenesis and diffuse intimal thickening may involve primarily smooth muscle cell hyperplasia with increased overall collagen production but little alteration in cell phenotype as regards the relative proportions of the individual collagens produced. They do not support the contention that atherosclerosis involves a 'transformation' of smooth muscle cells to fibroblast in type, whereby a major switch in synthesis occurs from largely type III collagen to mainly type I in disease. Type V collagen(s) containing both alpha A- and alpha B-chains has been detected throughout the vessel wall in diffusely thickened intima, media and adventitia, as well as in the plaque where, in the latter case, a marked enrichment relative to interstitial collagens was noted. This is presumed to reflect the relatively cellular nature of the atherosclerotic lesion. The alpha C-chain of type V collagen was detected in porcine but not human aorta.
Atherosclerosis 1982 Mar
PMID:Collagen polymorphism in the normal and diseased blood vessel wall. Investigation of collagens types I, III and V. 708 17

We have investigated the toxicity of the cholesterol oxidation products (oxysterols), 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, 7-ketocholesterol, 25-hydroxycholesterol and 26-hydroxycholesterol to human monocyte-macrophages in vitro. The 7-position derivatives are present in low density lipoprotein (LDL) oxidised with copper (II) sulphate and macrophages, and in extracts of human atherosclerotic lesions, which also contain 26-hydroxycholesterol. We have also assessed 25-hydroxycholesterol for toxicity because it has often been used in studies of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibition and LDL receptor down-regulation. Measurement of radioactivity release from monocyte-macrophages preloaded with tritiated adenine, as a means of assessing cytotoxicity that all the oxysterols showed time- and concentration-dependent toxicity. The cytotoxic potency of 26-hydroxycholesterol was the greatest. The 7-position derivatives also produced marked cell damage, though at higher concentrations than for 26-hydroxycholesterol. Of the oxysterols assessed, the toxicity of 25-hydroxycholesterol was the least. The cytotoxicity of 7 beta-hydroxycholesterol and 26-hydroxycholesterol was also shown using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) dye reduction assay which confirmed that 26-hydroxycholesterol was more toxic than 7 beta-hydroxycholesterol. Incubation of monocyte-macrophages with cholesterol added to the different oxysterols gave varying results. Cholesterol, which was not itself toxic, inhibited the toxicity of 25-hydroxycholesterol and 26-hydroxycholesterol, but the toxicity of the 7-position derivatives was not affected. The possible relevance of these molecules to the death of macrophages seen in atherosclerosis is discussed.
Atherosclerosis 1995 Nov
PMID:Toxicity of oxysterols to human monocyte-macrophages. 857 33

The immunoreactivity of high density lipoprotein (HDL) modified by treatment with porcine pancreatic phospholipase A2 (PLA2) was studied in a competitive radioimmunoassay using 6 different monoclonal apolipoprotein (apo) A-I antibodies. The competition tests have shown that after PLA2 treatment the immunoreactivity of selected epitopes of apo A-I changed in different ways. While the binding behavior of two epitopes remained unchanged, three epitopes exhibited decreased immunoreactivities after phospholipids hydrolysis. In contrast to the latter epitopes, the immunoreactivity of an epitope located on the cyanogen bromide fragment 4 of apo A-I increased with the degree of lipolysis. A loss of apo A-I from HDL as a consequence of PLA2-treatment did not occur as shown by the determination of the apo A-I concentration in HDL before and after treatment with PLA2. Using overlapped synthetic decapeptides it could be shown that the epitope increasingly exposed on the particle surface of PLA2-modified HDL consists of the amino acid residues 162-173 and 212-229. These residues are characterized by high hydrophobic indices as determined by hydropathy analysis. Furthermore, these regions belong partially to the proposed receptor-binding domain of apo A-I. Thus, an increased exposition of this epitope might result in elevated cellular binding affinities of HDL occurring after modification of lipoproteins by PLA2-treatment.
Atherosclerosis 1995 Oct
PMID:Changes in epitope exposition of apolipoprotein A-I on the surface of high density lipoproteins after phospholipase A2 treatment. 880 61

In this study we asked whether the well-known atherosclerosis resistance of rats might be reduced with aging. Two groups of young, adult and aged Wistar rats, one of which was kept on a standard, low-cholesterol (CT) diet, and the other one was fed a 2% CT diet for 2 months were enrolled. Potential modifications in the phenotypic profile of aortic smooth muscle (SM) were assessed by SDS-gel electrophoresis, Western blotting and immunofluorescence procedures using a panel of monoclonal antibodies to myosin isoforms, cytoskeletal and extracellular matrix proteins. With development and aging, the expression of 196-kD non-muscle-type myosin heavy-chain isoform (MyHC), the EIIIA fibronectin variant and keratins was downregulated, whereas that of the 204- and 200-kD SM-type MyHC isoforms, SM-type alpha-actin and desmin did not change. The levels of hypercholesterolemia achieved in this model did not substantially modify the distribution of the downregulated markers, except for the subendothelial grouping of immature SM cells in aged rats. Morphometric measurements indicated a slight increase of medial cross-sectional area accompanied by a decrease in total SM cell number, both with aging and with hypercholesterolemia. In no circumstance was the presence of atherosclerotic lesions histologically detectable. Bromo-deoxyuridine (BrdU) incorporation analysis revealed a marked age-dependent decline in DNA synthesis and the formation of binucleated cells in aged aortas. This pattern was not influenced by hypercholesterolemia, except in aged rats where BrdU-positive SM cells are almost doubled. Our data indicate that aging and hypercholesterolemia cannot affect the phenotypic stability of rat SM cells and confirm that the change from a fully differentiated to an immature state is a general prerequisite to allow the development of atherosclerotic lesions in mammalian species.
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PMID:Atherosclerosis resistance in rats correlates with lack of expansion of an immature smooth muscle cell population. 925 93

The effects of arachidonic acid metabolism and NADPH oxidase inhibitor on the hydrogen peroxide (H2O2) generation and endocytotic activity of cultured human endothelial cells (EC) exposed to atherogenic low-density lipoprotein (LDL) levels have been investigated. EC were incubated with 240 mg/dl LDL cholesterol and cellular H2O2 production and endocytotic activity measured in the presence and absence of the arachidonic acid metabolism inhibitors, indomethacin, nordihydroguaiaretic acid, and SKF525A, and NADPH oxidase inhibitor, apocynin. All inhibitors, with the exception of indomethacin, markedly reduced high LDL-induced increases in EC H2O2 generation and endocytotic activity. EC exposed to exogenously applied arachidonic acid had cellular functional changes similar to those induced by high LDL concentrations. EC incubated with 1-25 uM arachidonic acid had increased H2O2 production and heightened endocytotic activity. Likewise, EC pre-loaded with [3H]arachidonic acid when exposed to increasing LDL levels (90-330 mg/dl cholesterol) had a dose-dependent rise in cytosolic [3H]arachidonic acid. The phospholipase A2 inhibitors, 4-bromophenacyl bromide and 7,7-dimethyleicosadienoic acid, markedly inhibited H2O2 production in EC exposed to 240 mg/dl LDL cholesterol. These findings suggest that arachidonic acid contributes mechanistically to high LDL-perturbed EC H2O2 generation and heightened endocytosis. Such cellular functional changes add to our understanding of endothelial perturbation, which has been hypothesized to be a major contributing factor in the pathogenesis of atherosclerosis.
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PMID:Low-density lipoprotein stimulated peroxide production and endocytosis in cultured human endothelial cells: mechanisms of action. 927 82

To clarify the mechanism of cellular injury through the nonenzymatic reaction of glucose with proteins, we studied the cytotoxic effect of glycated bovine serum albumin on cultured smooth muscle cells in the presence of cupric ion. Glycated proteins were prepared by incubating bovine serum albumin with 0.5 M D-glucose in 0.3 M sodium phosphate buffer at 37 degrees C for 2, 4 and 16 weeks (g-BSA-2, g-BSA-4 and g-BSA-16, respectively). Early glycation products, such as fructosamine, were formed more than two weeks after incubation. However, the immunoreactivity of glycated proteins to anti-AGE antibody was 12-fold higher in g-BSA-16 than in g-BSA-2. Both g-BSA-2 and g-BSA-16 showed a concentration-dependent cytotoxicity in smooth muscle cells in the presence of 80 microM cupric ion by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) dye reduction assay and dye exclusion test. Flow cytometry and spectrofluorophotometry using dihydrorhodamine 123 showed that the extracellular generation of oxidants was dose-dependently enhanced with increasing concentrations of g-BSA-2 or g-BSA-16 in the presence of cupric ion. However, no difference was observed in the intracellular generation of oxidants between the presence and absence of glycated proteins by flow cytometry using 2', 7'-dichlorofluorescein diacetate. Cytotoxicity and oxidant generation were prevented by catalase and tiron, but not by superoxide dismutase or mannitol, a hydroxyl radical scavenger. These results indicate that smooth muscle cells may be damaged by reactive oxygen species which are produced extracellularly by the interaction with the early glycation products and cupric ion, and suggest that hydrogen peroxide may be a candidate for reactive oxygen species which contribute to such oxidative damage of smooth muscle cells.
Atherosclerosis 1998 Feb
PMID:Oxidative damage of vascular smooth muscle cells by the glycated protein-cupric ion system. 954 97

Vascular smooth muscle cell (VSMC) migration participates in atherosclerosis and arterial restenosis after balloon angioplasty. Because these processes are enhanced in insulin-resistant states, our goal was to determine whether insulin affects VSMC migration and, if so, how. The migration of primary cultured VSMCs from canine femoral artery was measured with the use of a wound migration assay and related to cGMP levels. Insulin (1 nmol/L) did not affect migration or cGMP production in control cells. When inducible nitric oxide synthase (iNOS) was induced by 24-hour preincubation with lipopolysaccharide and interleuken-1beta, basal migration decreased, cGMP production increased, and insulin inhibited migration by >90% and stimulated cGMP production by 3-fold. The nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine blocked the affect of insulin on the migration of VSMCs with iNOS. 8-Bromo-cGMP inhibited VSMC migration in control cells, and 1-H-1[1,2,4]oxadiazolo-[4, 3a]quinoxolin-1-one, a selective inhibitor of guanylate cyclase, blocked the inhibition by insulin of migration of cells with iNOS. We conclude that insulin does not normally affect cGMP production or the migration of these VSMCs. However, after the induction of iNOS, insulin stimulates cGMP production and inhibits migration via an NOS-and a cGMP-dependent mechanism.
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PMID:Insulin inhibits migration of vascular smooth muscle cells with inducible nitric oxide synthase. 1064 15


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