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)

Lipoprotein(a) (Lp[a]) is a low density lipoprotein particle that contains plasminogen-like apolipoprotein(a). Recent studies suggest an association of Lp(a) with atherosclerotic vascular disease. We have studied the accumulation of Lp(a) in atherosclerotic arteries of monkeys with diet-induced atherosclerosis. Immunohistochemistry with monospecific Lp(a) antisera revealed striking accumulations of Lp(a) in atherosclerotic coronary artery lesions. There was no Lp(a) in the normal, nonatherosclerotic arteries. Analysis of paired tissue and serum samples from 17 male hyperlipoproteinemic monkeys revealed a significant correlation between aortic wall Lp(a) and serum Lp(a) levels. The serum cholesterol level failed to correlate with either aortic Lp(a) or serum Lp(a). These results add further evidence for the potential role of Lp(a) in the pathogenesis of atherosclerosis.
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PMID:Lipoprotein(a) in diet-induced atherosclerosis in nonhuman primates. 182 15

The plasma concentration of lipoprotein (a) [Lp(a)] is correlated with the risk of atherosclerosis. It is a lipoprotein particle consisting of apoprotein (a) [Lp(a)] is correlated with the risk of atherosclerosis. It is a lipoprotein particle consisting of apoprotein (a) [apo(a)], a protein showing considerable amino acid sequence identity with plasminogen. bound to low-density lipoprotein. The apo(a) portion of Lp(a) was recently shown to have serine-proteinase-type amidolytic activity and to be able to degrade the adhesive glycoprotein fibronectin. To characterize this enzyme activity further, we used chromogenic peptide substrates and inhibitors. Of the substrates tested, those with arginine at the scissile bond [N-alpha-benzoyl-L-Arg p-nitroanilide (pNA), N-alpha-benzoyl-Ile-Glu-Gly-Arg-pNA, N-alpha-benzyloxycarbonyl-Arg-Gly-Arg-pNA] gave the highest hydrolysis rates. Synthetic substrates with plasmin specificity (Val-Leu-L-Lys-pNA and Val-Phe-L-Lys-pNA) were not hydrolysed by Lp(a). Neither tissue plasminogen activator nor urokinase had any effect on the enzyme activity. The addition of antibodies to these plasminogen activators did not inhibit the enzyme activity of Lp(a). Inhibition experiments with phenylmethanesulphonyl fluoride, carbodi-imide, dichloroisocoumarin and competitive peptide inhibitors demonstrated that Lp(a) has enzyme activity that closely resembles that of serine proteinases. Whether this serine-proteinase activity of Lp(a) plays any role in the genesis of atherosclerosis remains to be established.
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PMID:Characterization of the enzyme activity of human plasma lipoprotein (a) using synthetic peptide substrates. 182 80

Apoprotein(a), (apo[a]), the specific antigen of lipoprotein(a) (Lp[a]), consists of structural domains (a serine protease unit, kringles 4 and 5) with marked homology to those of the corresponding domains in plasminogen. In this study, we have investigated the impact of this unique structural mimicry on the binding and activation of plasminogen by fibrin-bound tissue-type plasminogen activator at the plasma-fibrin interface. We found that the total amount of plasmin generated on the surface of fibrin was decreased in the presence of high concentrations of Lp(a): 197 +/- 65 fmol in plasmas with greater than 60 mg/dl Lp(a) versus 287 +/- 112 fmol in control plasmas. A similar effect was also apparent in the corresponding euglobulin fractions (554 +/- 169 fmol versus 754 +/- 310 fmol), the latter lacking the plasminogen-binding proteins alpha 2-antiplasmin and histidine-rich glycoprotein, but containing Lp(a). The difference between plasma samples was significant (p less than 0.05) as calculated from the percent decrease in plasmin generated from plasmas with high levels of Lp(a) relative to that generated in the paired controls with low Lp(a) levels. The involvement of Lp(a) was verified in a reconstituted system consisting of normal human plasma supplemented with 100 mg/dl of either purified Lp(a) or low density lipoprotein. Lp(a) produced a decrease of 30% in the generation of plasmin (180 fmol versus 255 fmol in plasma, and 485 fmol versus 705 fmol in the euglobulin fraction). Moreover, using a radiolabeled sheep antibody against human apo(a), we were able to demonstrate the binding of 40 fmol Lp(a) to fibrin during ongoing plasminogen activation. These results indicate that Lp(a) impairs the binding of plasminogen to fibrin and thereby decreases the generation of plasmin by occupying C-terminal lysine residues unveiled on the fibrin surface by plasmin degradation as recently reported (Circulation 1990;82[suppl III]:III-92). In consequence, impairment of fibrinolysis and accumulation of Lp(a) at sites of vascular injury may occur, factors that may be important in the development of atherosclerosis and associated thrombosis.
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PMID:Lipoprotein(a) impairs generation of plasmin by fibrin-bound tissue-type plasminogen activator. In vitro studies in a plasma milieu. 182 91

Plasma concentrations of lipoprotein (a) (Lp(a)) were studied in 11 male alcoholics at the end of a drinking period and monitored during subsequent abstinence. Lp(a) levels showed a daily increase for four consecutive days after the beginning of abstinence, the values for the third and the fourth day being significantly higher than those of the first day (p less than 0.05 and p less than 0.01, respectively). The changes in Lp(a) showed no association with the changes in low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol levels. In one alcoholic subject with a heterozygous form of familial hypercholesterolemia who was monitored for 11 days, the Lp(a) levels rose up to the fourth day and remained at a high level thereafter. These results suggest that ethanol ingestion may be associated with a lowering of Lp(a) levels, which may contribute to the delayed progression of atherosclerosis observed in alcohol drinkers. Ethanol intake may be added to the short list of factors that affect the quite stable, genetically determined Lp(a) concentrations in the plasma.
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PMID:A rapid increase in lipoprotein (a) levels after ethanol withdrawal in alcoholic men. 182 57

Levels of Lipoprotein(a) [Lp(a)] correlate directly with atherosclerosis risk. The Lp(a) particle is physically and chemically similar to low density lipoprotein (LDL), the main difference being the presence of apolipoprotein(a) [apo(a)] bonded to the apoB-100 moiety of LDL. Genetic variation of apo(a) primarily determines Lp(a) phenotype. However, other genetic factors may also have a role in determining Lp(a) levels. Large families provide a unique opportunity to evaluate the contribution of genetic factors to disease. In several large Utah kindreds with various genetic abnormalities of lipoprotein metabolism we determined that: 1) Lp(a) levels are associated with defects at the apoB gene; 2) Lp(a) levels are not associated with defects at the LDL-receptor gene; 3) high density lipoprotein (HDL) levels are associated with genetic variation at the apo(a) locus; and 4) the DNA sequence of the apoB-100 binding domain does not vary between siblings with high and low Lp(a) levels.
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PMID:The effect of genetic determinants of low density lipoprotein levels on lipoprotein (a). 182 2

Plasma lipoprotein(a), Lp(a), is the most important known genetically controlled independent risk factor for the prediction of early atherosclerosis (AS) and coronary artery disease (CAD) in a significant subpopulation of Caucasians. A sensitive, specific 'capture' enzyme linked immunosorbent assay (ELISA) is reported for the assay of human plasma Lp(a). There is no interference from low density lipoprotein (LDL), plasminogen, or from endogenous lipids, hemoglobin, or bilirubin. An immobilized polyclonal rabbit antibody 'captures' the Lp(a) ligand, and then a monoclonal murine antibody 'recognizes' it. Alkaline phosphatase conjugated rabbit antimouse IgG and para-nitrophenyl phosphate substrate 'detect' and 'indicate' colorimetrically the amount of Lp(a) bound. Quantitation is relative to a commercially available secondary clinical standard. The frequency distribution for a predominantly Caucasian reference population is highly skewed toward the higher concentrations. The median plasma Lp(a) concentration for healthy Caucasians is 80 mg per 1. Relative risk for early myocardial infarction (MI) increases as plasma Lp(a) levels increase above 300 mg per 1. Approximately 20 percent of Caucasians have plasma Lp(a) values above 300 mg per 1. The frequency distributions of plasma Lp(a) in Blacks and Caucasian type II diabetics are different from the healthy Caucasian reference population. The percentiles of Lp(a) values greater than 300 mg per 1 in these latter groups is three times higher. Thorough epidemiologic and clinical studies where groups are segregated by race and ethnic origin are needed for accurate clinical interpretation of plasma Lp(a) results. Only neomycin and niacin are shown to lower plasma Lp(a) levels therapeutically, although anabolic steroid medication causes lower plasma Lp(a) concentrations. Endocrine malfunction also may influence plasma Lp(a) levels.
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PMID:Human lipoprotein(a) quantified by 'capture' ELISA. 182 98

Homozygous familial hypercholesterolemia (FH) is a genetic disorder featuring a functional defect in cellular LDL receptors, marked elevation in circulating LDL concentrations, and premature atherosclerosis. The potential atherogenic role of apo B-containing lipoproteins other than LDL in this disease is indeterminate. We describe the quantitative and qualitative characteristics of Lp(a) as a function of apo(a) phenotype in a group of eight, unrelated homozygous FH patients. Plasma Lp(a) levels were significantly elevated (2.5-fold; mean 50 +/- 32 mg/dl) as compared to those in healthy subjects. The S2 isoform of apo(a) occurred most frequently (6 of eight patients); the rare B isoform presented in three patients. Plasma Lp(a) levels in homozygous FH did not correspond to those predicted by apo(a) phenotype. Analyses of the density distribution of Lp(a) and of Lp(a) particle size and heterogeneity as a function of density did not reveal any anomalies characteristic of homozygous FH. However, comparison of the hydrated density of Lp(a) particles as a function of apo(a) isoform content revealed a clear influence of isoform on this parameter; thus, in a B/S2 heterozygous patient, the density distribution of Lp(a) fractions containing isoform B alone, B and S2, and S2 alone, demonstrated that the apparent molecular weight of apo(a) plays a determining role in controlling the hydrated density and size of the resulting Lp(a) particle. Indeed, patients expressing the high molecular weight, S2 isoform uniformly displayed a dense form of Lp(a) (hydrated density approximately 1.055 g/ml). In subjects presenting two apo(a) isoforms, each isoform resided on distinct lipoprotein particles; in such cases, the plasma levels of the denser isoform predominated, suggesting differences in rates of formation, or rates of tissular catabolism, or in the plasma stability of the particles, or a combination of these mechanisms. Considered together, our data may be interpreted to suggest that the elevated circulating levels of Lp(a) in homozygous FH patients may reflect either an increased biosynthesis, or diminished catabolism via the cellular LDL receptor pathway, or a combination of both.
Atherosclerosis 1991 Jan
PMID:Lipoprotein Lp(a) in homozygous familial hypercholesterolemia: density profile, particle heterogeneity and apolipoprotein(a) phenotype. 182 9

The in vivo turnover of autologous lipoprotein(a) (Lp(a)) was studied in four heterozygous familial hypercholesterolaemic (FH) subjects and four subjects who were hyperlipidaemic but not FH. Each of the FH subjects exhibited a much lower fractional catabolic rate (FCR) for LDL than each of the non-FH subjects. Lp(a) was purified by sequential density gradient centrifugations and was radio-iodinated. The labelled Lp(a) ran as a single band on electrophoresis in gradient polyacrylamide gels. Less than 5% of the label was in lipid, with about 40% of the remainder on apolipoprotein B (apo B) and 60% on apo(a). Labelled and unlabelled Lp(a) competed equally poorly with LDL for binding to LDL receptors on cultured fibroblasts. The FCR of Lp(a), calculated from the decay of the specific radioactivity of the Lp(a) isolated from the daily blood samples, was the same in FH subjects as in non-FH subjects. There was no consistent relationship between Lp(a) FCR and the plasma Lp(a) concentration or between FCR and the Lp(a) phenotype, at least within this sample of subjects. There was a strong association between Lp(a) concentration and production rate, with values for non-FH and FH subjects falling on the same line. The rate of decline of radioactivity in whole plasma was consistently slower than the fall in specific radioactivity of the isolated Lp(a). This difference was more marked in FH subjects than in non-FH subjects and resulted from the accumulation of radioactivity derived from the injected Lp(a) at a lower density than Lp(a), in the fractions containing LDL. The amount of radioactivity in this fraction increased for the first few days after injection and then fell, the fall being more rapid in non-FH than in FH subjects. These results provide no evidence for the involvement of LDL receptors in the catabolism of Lp(a) itself but suggest that they could be responsible for some of the clearance of the lipid and apo B components after removal of apo(a) in the circulation.
Atherosclerosis 1991 Apr
PMID:Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects. 183 Feb 6

The cynomolgus macaque was used as a model to study lipoprotein(a) (Lp(a)). Antibodies to Lp(a) were used in Ouchterlony and Western blot analysis to show that cynomolgus monkey and human Lp(a) were similar immunochemically. Monkey Lp(a) levels were measured by a quantitative sandwich enzyme-linked immunosorbent assay in 117 animals, and Lp(a) varied in concentration from 1 to 64 mg/dl. Individual monkeys had apo(a) glycoprotein sizes as either single- or double-band phenotypes that ranged from 400 to 750 kDa. Monkey apo(a) transcript lengths varied from 8.5 to 13.6 kilobases. The Lp(a) concentration, apo(a) glycoprotein size, and apo(a) transcript length distributions were similar to those in humans. In the monkeys, there was a very high correlation between apo(a) transcript size and apo(a) protein size (R = 0.93, p = 0.0001). This variation in apo(a) transcript and protein size was shown to be due to the number of kringle IV repeats in apo(a) mRNA and DNA. Monkey plasma Lp(a) concentrations correlated inversely with apo(a) glycoprotein size (R = 0.43, p = 0.0016) and directly with hepatic apo(a) mRNA abundance (R = 0.54, p = 0.004). Apo(a) transcript lengths did not correlate with hepatic apo(a) mRNA levels. This suggests that apo(a) size and mRNA levels have major independent effects on plasma Lp(a) concentration. In multivariate analysis, they account for up to 58% of the variability in Lp(a) concentration. In summary, these data provide insight into the regulation of Lp(a) levels and suggest that the cynomolgus monkey is a suitable model in which to study the role of Lp(a) in the pathogenesis of atherosclerosis.
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PMID:Plasma lipoprotein(a) concentration is controlled by apolipoprotein(a) (apo(a)) protein size and the abundance of hepatic apo(a) mRNA in a cynomolgus monkey model. 183 Mar 9

Lipoprotein (Lp)(a) concentrations were measured in eight patients with nephrotic syndrome in the age range of 8 to 69 yrs. Mean (+/- SE) levels of serum Lp(a) were elevated in the nephrotic patients compared to controls (76.5 +/- 19.7 vs 18.6 +/- 0.9 mg/dl, p less than 0.001). After treatment with prednisolone, Lp(a) concentrations were decreased from 85.2 +/- 21.6 to 42.2 +/- 14.0 mg/dl. During the treatment, serum total cholesterol showed a negative correlation with serum albumin concentration. However, no correlation was noted between Lp(a) and serum albumin concentration. There were no significant correlations between Lp(a) and other lipoprotein lipid and apolipoprotein levels. It was concluded that hyperLp(a)aemia may be an independent risk factor in the development of premature atherosclerosis in patients with nephrotic syndrome.
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PMID:A study of the clinical significance of lipoprotein (a) in nephrotic syndrome. 183 Sep 8


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