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)

Apolipoprotein E is a secretory glycoprotein that associates with lipoprotein particles and is coded for by a single locus on chromosome 19. The three common allelic isoforms of this protein (apo E2, apo E3 and apo E4) are associated with distinct patterns of lipoprotein metabolism and variable risks for coronary artery disease. In addition, recent work has shown that the presence of the apo E4 isoform constitutes a major risk for developing late-onset Alzheimer's disease as well as hypercholesterolaemia. The only differences between these isoforms result from cysteine-arginine interchanges at codons 112 and 158. There is considerable disagreement in the literature concerning the identity of the ancestral allele. In order to resolve this, 24 chimpanzees and individuals from a number of other primate species were analysed. All were similar to apo E4. This suggests that apo E4 is the ancestral allele and that apo E2 and apo E3 arose after the split of the human and chimpanzee lineages.
Atherosclerosis 1995 Jan 06
PMID:Arginine residues at codons 112 and 158 in the apolipoprotein E gene correspond to the ancestral state in humans. 777 71

The action of gypenosides (GP, saponins of Gynostemma pentaphyllum, a Chinese medicinal herb) as an antioxidant was studied using various models of oxidant stress in phagocytes, liver microsomes and vascular endothelial cells. The results show that GP decreased superoxide anion and hydrogen peroxide content in human neutrophils and diminished chemiluminescent oxidative burst triggered by zymosan in human monocytes and murine macrophages. An increase of lipid peroxidation induced by Fe2+/cysteine, ascorbate/NADPH or hydrogen peroxide in liver microsomes and vascular endothelial cells was inhibited by GP. It was also found that GP protected biomembranes from oxidative injury by reversing the decreased membrane fluidity of liver microsomes and mitochondria, increasing mitochondrial enzyme activity in vascular endothelial cells and decreasing intracellular lactate dehydrogenase leakage from these cells. The extensive antioxidant effect of GP may be valuable to the prevention and treatment of various diseases such as atherosclerosis, liver disease and inflammation.
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PMID:Protective effect of gypenosides against oxidative stress in phagocytes, vascular endothelial cells and liver microsomes. 780 67

Homocysteine (HCY), which is derived from the intracellular metabolism of methionine, is exported into plasma, where it circulates mostly in oxidized forms (i.e., homocystine and cysteine-HCY disulfide) and mainly bound to proteins. Concentrations of total HCY, or homocyst(e)ine [H(e)], are increased in 15-40% of patients with coronary, cerebral, or peripheral arterial diseases. Such association of H(e) with arterial occlusive diseases has been documented in retrospective, cross-sectional, and prospective studies. Concentrations of H(e) are also increased in subjects having thickened carotid arteries, as determined by ultrasonography, and who are asymptomatic for atherosclerosis. Statistical analyses of data from several series of patients demonstrate that H(e) concentrations are associated with coronary artery disease, independently from most other risk factors for atherosclerosis. The increased concentrations of H(e) are readily corrected by folic acid, occasionally supplemented with pyridoxine, vitamin B12, choline, or betaine. Whether these supplements affect the evolution of atherosclerotic disease needs to be established by prospective, placebo-controlled clinical trials.
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PMID:Plasma homocyst(e)ine and arterial occlusive diseases: a mini-review. 781 76

The oxidative modification of low-density lipoprotein by macrophages may be an important mechanism in the pathogenesis of atherosclerosis. The human monocytic leukaemia cell line THP-1, when stimulated with phorbol ester, shares many properties with human monocyte-derived macrophages. Oxidation of LDL by these cells was characterised by depletion of alpha-tocopherol, increases in thiobarbituric acid reactive substances and increases in electrophoretic mobility. The LDL particles were also converted to a form which increased accumulation of cholesteryl esters within macrophages. The oxidative mechanism appeared to be dependent upon the presence of thiols in the cellular medium. Oxidation of LDL by THP-1 macrophages, and production of thiols by these cells, were dependent upon the presence of L-cystine in the medium. Furthermore, cellular oxidation of LDL could be partially mimicked by the addition of cysteine to Hams F10 medium. Macrophage-independent oxidation of LDL, mediated by the addition of copper ions, was inhibited by cystine and cysteine in phosphate buffered saline, but not in Hams F10 medium. The glutathione content of THP-1 macrophages was also dependent upon the presence of cysteine or cystine in the medium, but inhibition of glutathione synthesis by buthionine sulfoximine did not prevent the production of thiols or the oxidation of LDL by THP-1 macrophages.
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PMID:Human (THP-1) macrophages oxidize LDL by a thiol-dependent mechanism. 888 36

Low density lipoprotein (LDL) oxidation within the arterial wall may contribute to the disease of atherosclerosis. We have investigated the conditions under which transferrin (the major iron-carrying protein in plasma) may release iron ions to catalyse the oxidation of LDL. Transferrin that had been incubated at pH 5.5 released approximately 10% of its bound iron in 24 h, as measured by ultrafiltration and atomic absorption spectroscopy. Furthermore, transferrin co-incubated with LDL and L-cysteine at pH 5.5 resulted in the oxidation of the LDL as measured by thiobarbituric acid-reactive substances and electrophoretic mobility. This effect was observed at transferrin concentrations as low as 40% of its average plasma concentration. The release of iron from transferrin in atherosclerotic lesions due to a localised acidic pH may help to explain why LDL oxidation occurs in these lesions.
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PMID:Iron released from transferrin at acidic pH can catalyse the oxidation of low density lipoprotein. 792 32

Elevated levels of lipoprotein(a) (Lp(a)) have been strongly correlated with the development of atherosclerosis in human populations. Lp(a) is distinguishable from low density lipoprotein by the presence of the unique protein component apolipoprotein(a) (apo(a)), which contains repeated domains that closely resemble that of plasminogen kringle IV. Using human embryonic kidney cells, we have expressed a recombinant form of apo(a) (r-apo(a)) containing 17 kringle IV-like domains. We have utilized this recombinant expression system to study the assembly of Lp(a) particles. We have demonstrated that Lp(a) particles containing r-apo(a) can be assembled extracellularly in plasma by covalent linkage to low density lipoprotein. Using site-directed mutagenesis, we have demonstrated that a cysteine residue present at position 4057 of the apo(a) protein (i.e., in the penultimate kringle IV repeat) mediates this covalent linkage. Using polymerase chain reaction amplification of liver apo(a) complementary DNA, we have demonstrated the presence of a polymorphism in apo(a) kringle IV type 10, which results in the substitution of a threonine for a methionine. Preliminary studies indicate that the presence of a threonine at this position may enhance the interaction of Lp(a) with lysine-Sepharose.
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PMID:Analysis of structure--function relationships in human apolipoprotein(a). 806 77

Apo(a) is a low density lipoprotein homologous to plasminogen and has been shown to be involved in coronary atherosclerosis. In the present paper we will try to analyze the interesting evolutionary pattern of Apo(a). The plasminogen gene contains 5 cysteine-rich sequences, called kringles, followed by a protease domain. Apo(a), probably arisen by duplication of an ancestral plasminogen gene, contains many tandemly repeated copies of a sequence domain similar to the fourth kringle of plasminogen, 37 in human and at least 10 in the partially sequenced gene of rhesus, and the protease domain. We have found that the upstream kringles of apo(a) undergo Molecular Drive-like processes that produce high intraspecies similarity, whereas the downstream kringles evolve in a molecular clock-like manner and show an high interspecies sequence similarity. The latter regions are obviously suitable for dating the duplication event by which Apo(a) arose from plasminogen, but only if they evolve at the same rate in the two genes. Thus, we propose a "Molecular Clock Test" for assessing whether the comparison of two paralogous genes (or gene regions) can give reliable information on the dating of their origin by duplication. Applying this test to the kringle-4 domain of apo(a) and plasminogen gene, we demonstrate that the separation between the two genes by duplication dates back at about 90 Mya immediately before the radiation of mammals.
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PMID:The peculiar evolution of apolipoprotein(a) in human and rhesus macaque. 813 62

The endothelial surface plays an important role in the pathogenesis of atherosclerosis and the regulation of coagulation. It has become increasingly clear that while perturbed endothelial cells generate procoagulant activity, under normal conditions they possess multiple antithrombotic and anticoagulant mechanisms, including generation of prostacyclin and plasminogen activators and synthesis of thrombomodulin as a cell surface cofactor for thrombin-catalyzed activation of protein C. In addition, anticoagulantly active heparan sulfate proteoglycans, including heparin-like molecules are apparently present on the vascular surface. Previous studies showed that homocysteine, a thromboatherogenic and atherogenic agent, inhibits an endothelial thrombomodulin-protein C anticoagulant pathway. We examined whether homocysteine might affect another endothelial anticoagulant mechanism; i.e., heparin-like glycosaminoglycan-antithrombin III interactions. Incubations of cultured endothelial cells with homocysteine reduced the amount of antithrombin III bound to the cell surface in a dose- and time-dependent fashion. In contrast with a marked reduction in the maximal antithrombin III binding capacity, the radioactivity of [35S] sulfate incorporated into heparan sulfate on the cell surface was minimally reduced. Although neither net negative charge nor proportion in total glycosaminoglycans of cell surface heparan sulfate was altered by homocysteine treatment, a substantial reduction in antithrombin III binding capacity of heparan sulfate isolated from homocysteine-treated endothelial cells was found using both affinity chromatography and dot blot assay techniques. The antithrombin III binding activity of endothelial cells decreased after preincubation with homocysteine, cysteine, or 2-mercaptoethanol, containing a sulfhydryl group; no reduction in binding activity was observed after preincubation with methionine, alanine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Heparan sulfate proteoglycan of endothelial cells: homocysteine suppresses anticoagulant active heparan sulfate in cultured endothelial cells]. 817 41

Nitric oxide reacts with superoxide to form peroxynitrite, a potential mediator of oxidant-induced cellular injury. The endothelium is a primary target of injury in many pathological states, including acute lung injury, sepsis, multiple organ failure syndrome, and atherosclerosis, where enhanced production of nitric oxide and superoxide occurs simultaneously. It was hypothesized that stimulation of endothelial cell nitric oxide production would result in formation of peroxynitrite. Immediate oxidant production was detected by luminol- and lucigenin-enhanced chemiluminescence from cultured bovine aortic endothelial cells exposed to bradykinin or to the calcium ionophore A23187. Luminol-enhanced chemiluminescence was efficiently inhibited by the nitric oxide synthase inhibitor nitro-L-arginine methyl ester and by superoxide dismutase, implying dependence on the presence of both nitric oxide and superoxide for oxidant production. Inhibition of luminol-enhanced chemiluminescence by nitro-L-arginine methyl ester was partially reversed by L-arginine, but not by D-arginine. Cysteine, methionine, and urate, known inhibitors of peroxynitrite-mediated oxidation, inhibited luminol-enhanced chemiluminescence, while the hydroxyl radical scavengers, mannitol and dimethylsulfoxide, and catalase did not. Bicarbonate increased luminol-enhanced chemiluminescence in a concentration-dependent manner. Superoxide production, detected by lucigenin-enhanced chemiluminescence, was slightly increased in the presence of nitro-L-arginine methyl ester, suggesting that endothelial cell-produced superoxide was partially metabolized by reaction with nitric oxide. These results are consistent with agonist-induced peroxynitrite production by endothelial cells and suggests that peroxynitrite may have an important role in oxidant-induced endothelial injury.
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PMID:Agonist-induced peroxynitrite production from endothelial cells. 817 19

The effects of a high level of methionine on the changes of lipid and amino acid metabolism were investigated. Eighteen New Zealand White rabbits were divided into three groups; a methionine group, which was fed a diet supplemented with 3% D, L-methionine, a Cholesterol+Methionine group, which was fed a 3% D, L-methionine and a 0.2% cholesterol diet, and a Cholesterol group which was fed a 0.2% cholesterol diet for 22 weeks. The plasma triglyceride, cholesterol, homocysteine, cysteine and serum SO4(2-) levels were measured and compared. On the first and the final day of the experiment, lipid peroxide levels in blood samples were also measured. We found that the Methionine group and the Cholesterol+Methionine group showed elevated levels of plasma triglyceride, cholesterol, homocysteine, cysteine, serum SO4(2-) and lipid peroxide compared with the Cholesterol group. More prominent fat deposits in the aorta were observed in the Methionine group and the Cholesterol+Methionine group than in the Cholesterol group. Our results indicated that the interaction of cholesterol with methionine or its derivatives plays a role in the progression of atherosclerosis.
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PMID:[The influence of methionine and its metabolites on the progression of atherosclerosis in rabbits]. 855 Aug 5


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