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)

Apo E5(Glu3----Lys) is a naturally occurring apolipoprotein E (apo E) mutant found in patients with hyperlipoproteinemia and atherosclerosis. It has been shown to have a high affinity for low density lipoprotein (LDL) receptors. In this study, mutant apo E5 was produced by Chinese hamster ovary cells by means of an in vitro site-directed mutagenesis technique, and its LDL receptor binding activity was assessed. The apo E5 obtained from gene expression bound more readily to the LDL receptor than did plasma apo E3. The concentrations required for 50% competitive binding of 125I-labeled LDL to the LDL receptors were 58.9 ng/ml for plasma apo E3 and 25.7 ng/ml for the expressed apo E5. The expressed apo E5 displayed 229% normal binding. This result is highly consistent with that obtained with plasma apo E5, which showed 217% normal binding. Although the experimental apo E isoproteins contained more sialic acid than plasma apo E, the extent of sialylation had no effect on the receptor binding of apo E.
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PMID:Site-directed mutagenesis of an apolipoprotein E mutant, apo E5(Glu3----Lys) and its binding to low density lipoprotein receptors. 153 Jun 12

Changes in low density lipoprotein (LDL) lipid composition were shown to alter its interaction with the LDL receptor, thus affecting its cellular uptake. Upon incubation of LDL with 5 units/ml cholesterol esterase (CEase) for 1 h at 37 degrees C, there was a 33% reduction in lipoprotein cholesteryl ester content, paralleled by an increment in its unesterified cholesterol. CEase-LDL, in comparison to native LDL, was smaller in size, possessed fewer free lysine amino groups (by 14%), and demonstrated reduced binding to heparin (by 83%) and reduced immunoreactivity against monoclonal antibodies directed toward epitopes along the LDL apoB-100. Incubation of CEase-LDL with the J-774 macrophage-like cell line resulted in about a 30% reduction in lipoprotein binding and degradation in comparison to native LDL, and this was associated with a 20% reduction in macrophage cholesterol mass. Similarly, CEase-LDL degradation by mouse peritoneal macrophages, human monocyte-derived macrophages, and human skin fibroblasts was reduced by 20-44% in comparison to native LDL. CEase-LDL uptake by macrophages was mediated via the LDL receptor and not the scavenger receptor. CEase activity toward LDL was demonstrated in plasma and in cells of the arterial wall such as macrophages and endothelial cells. Thus, CEase modification of LDL may take place in vivo, and this phenomenon may have a role in atherosclerosis.
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PMID:Reduced uptake of cholesterol esterase-modified low density lipoprotein by macrophages. 171 Oct 36

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

Thrombotic occlusion is the major cause of myocardial infarction (MI), and fibrin accumulation appears to play a significant role in development of atherosclerotic lesions. Any factor that reduces the lysis of fibrin may thus increase the risk of MI, and it has been suggested that this accounts for the atherogenicity of the lipoprotein variant Lp(a). The characteristic feature of Lp(a) is an apoprotein which is homologous with part of the plasminogen molecule, and experiments in vitro suggest that it interferes with uptake and activation of plasminogen on cell surfaces and fibrin. The presence of Lp(a) also seemed to offer an explanation for the apparent absence of plasminogen from 70-80% of intimal samples. We have compared the levels of Lp(a) and plasminogen in normal intima and atherosclerotic lesions. In aortic intima there was no relation between Lp(a) and plasminogen, which was absent in some samples with no Lp(a), and present in others with high levels. In intravascular thrombi plasminogen was present at a rather constant concentration (16.3 +/- 4.6 micrograms/100 mg wet tissue), whereas Lp(a) varied over a 100 fold range (0-104 micrograms/100 mg). Plasminogen binds to fibrin and is activated on the fibrin clot, so levels in extracts may not fully represent Lp(a)/plasminogen interactions. After extraction the residual tissues and thrombi were treated with 1 M epsilon-aminocaproic acid (epsilon-aca) to elute lysine-bound components. Lp(a) was eluted from all but one intimal sample, confirming previous findings on its binding to fibrin in lesions, but there was no relation between the amounts of Lp(a) and plasminogen in the tissue eluates. Paradoxically, in the thrombi there was a weak positive correlation between Lp(a) and plasminogen in epsilon-aca eluates (r = 0.504, P = 0.05). These results do not support the hypothesis that Lp(a) displaces plasminogen in vivo, but the large amount of Lp(a) eluted by epsilon-aca suggests that its atherogenicity resides in preferential binding to fibrin, leading to increased lipid accumulation in lesions.
Atherosclerosis 1991 Aug
PMID:Does lipoprotein(a) (Lp(a)) complete with plasminogen in human atherosclerotic lesions and thrombi? 183 24

Previous studies have shown that nonenzymatic glycosylation of high-density lipoprotein (HDL) inhibits high-affinity binding to cultured cells and the candidate HDL-receptor protein. Because binding of HDL to its receptor is required for HDL-receptor-mediated cholesterol efflux from cells, we hypothesized that glycosylated HDL3 would have reduced ability to remove cholesterol from cells. HDL3 was glycosylated in vitro to achieve up to 40-50% reductions in free-lysine residues. Glycosylated HDL3 had a slightly greater ability than control HDL3 to sequester cholesterol directly from the plasma membrane, as predicted by changes in lipid composition. This process is independent of HDL-receptor binding and should not be influenced by reduced binding of HDL3. In contrast, efflux of intracellular cholesterol from cells, which is HDL-receptor dependent, was reduced 25-40%. The ability of glycosylated HDL3 to diminish cholesterol esterification was significantly reduced, indicating reduced net cholesterol efflux. Steady-state efflux of LDL-derived cholesterol was also markedly reduced. These findings suggest that nonenzymatically glycosylated HDL is functionally abnormal and might contribute to the accelerated development of atherosclerosis in patients with diabetes mellitus.
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PMID:Nonenzymatic glycosylation of HDL and impaired HDL-receptor-mediated cholesterol efflux. 184 86

The plasma concentration of lipoprotein (a) (Lp(a] varies widely in humans, and elevated concentrations of this lipoprotein are correlated with progression of atherosclerosis. Structural studies of Lp(a) have revealed that it is a low density lipoprotein (LDL)-like particle containing a unique glycoprotein, apo(a), which shares extensive homology with plasminogen. The apo(a) portion of Lp(a) binds to the carboxy-terminal heparin-binding domain of fibronectin. Incubation of Lp(a) or isolated apo(a) with fibronectin results in proteolytic cleavage of fibronectin which is, as visualized by gel electrophoresis and immunoblotting, distinct from that caused by plasmin or kallikrein. The proteolytic activity of apo(a) is of serine proteinase-type and displays specificity for arginine rather than lysine bonds. The molecular mechanism(s) underlying the association between Lp(a) and atherosclerosis remains an enigma.
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PMID:Interaction of lipoprotein(a) with fibronectin and its potential role in atherogenesis. 214 25

Nonenzymatic glycosylation of plasma proteins may contribute to the excess risk of developing atherosclerosis in patients with diabetes mellitus. Because high-density lipoprotein (HDL) is believed to protect against atherosclerosis and is glycosylated at increased levels in diabetic individuals, the effects of nonenzymatic glycosylation of HDL3 on binding of HDL3 to cultured fibroblasts and to the candidate HDL-receptor protein were examined. HDL3 was glycosylated in vitro with glucose alone or in combination with sodium cyanoborohydride. With this catalyst, up to 40-50% of the lysine residues could be glycosylated, resulting in a progressive drop to nearly 60% in high-affinity binding to cultured fibroblasts at 4 degrees C. Binding to the 110,000-Mr candidate HDL-receptor protein was reduced by almost 75%. At levels of HDL glycosylation equivalent to the 3-5% observed in diabetes, high-affinity binding to fibroblasts at 4 degrees C was diminished by up to 15-20%. Binding kinetic studies paradoxically suggested that glycosylated HDL3 binds with higher affinity to a reduced number of binding sites. The findings in this study suggest that nonenzymatically glycosylated HDL may be functionally abnormal and might contribute to the development of atherosclerosis in patients with diabetes mellitus.
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PMID:Nonenzymatic glycosylation of HDL resulting in inhibition of high-affinity binding to cultured human fibroblasts. 217 Feb 16

Oxidative modification of LDL is accompanied by a number of compositional and structural changes, including increased electrophoretic mobility, increased density, fragmentation of apolipoprotein B, hydrolysis of phosphatidylcholine, derivatization of lysine amino groups, and generation of fluorescent adducts due to covalent binding of lipid oxidation products to apo B. In addition, oxidation of LDL has been shown to result in numerous changes in its biologic properties that could have pathogenetic importance, including accelerated uptake in macrophages, cytotoxicity, and chemotactic activity for monocytes. The present article summarizes very recent developments related to the mechanism of oxidation of LDL by cells, receptor-mediated uptake of oxidized LDL in macrophages, the mechanism of phosphatidylcholine hydrolysis during LDL oxidation, and other biologic actions of oxidized LDL including cytotoxicity, altered eicosanoid metabolism, and effects on the secretion of growth factors and chemotactic factors. In addition, this review will examine the evidence for the presence of oxidized LDL in vivo and the evidence that oxidized LDL plays a pathogenetic role in atherosclerosis.
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PMID:Role of oxidatively modified LDL in atherosclerosis. 222 30

We analyzed serum lipoproteins and apolipoprotein E (apo E) from 199 patients in CCU, having ischemic heart disease, and from 211 healthy subjects. It was suggested that serum lipoprotein abnormalities, especially elevated low density lipoprotein (LDL) levels, are closely related to atherogenesis in relatively young patients and subjects with severe coronary lesions. The frequency of apo E-4 was higher and that of E-2 was lower in the CCU group than in the control group. Apo E mutants, E-7 (Glu244----Lys, Glu245----Lys) and E-5 (Glu3 (Glu3----Lys), were also frequent in the CCU group. Apo E isoproteins have higher pI in the order E-2, E-3, E-4, and we observed that LDL-cholesterol levels increased in the same order. The apo E mutants, E-5 and E-7, are also more basic than E-4. These findings suggest that basic apo Es were associated with the development of atherosclerosis. The prevalence of familial hypercholesterolemia (FH) in the CCU group was more than 10 times higher than the reported frequency of FH heterozygotes in normal population. The persistence of marked hypercholesterolemia from infancy probably makes FH patients susceptible to atherosclerosis. Based on the analysis of LDL-receptor protein synthesis, various types of mutations were observed even in phenotypically homozygous FH patients. FH homozygotes were divided into 2 groups, a receptor-negative group and a receptor-defective group. We found a great difference in the frequency of coronary heart disease depending on whether even a small number of receptors were present or not.
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PMID:Hyperlipoproteinemia as a risk factor for ischemic heart disease. 239 26


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