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)

Homocysteine is a thiol-containing amino acid resulting from demethylation of methionine. The free and protein-bound forms of the amino acid and derived disulfides are called homocyst(e)ine [H(e)]. Multiple studies have shown elevated H(e) levels in patients with coronary, cerebrovascular, or peripheral arterial diseases; this association is frequent and independent of most other risk factors for atherosclerosis. In the 1993 Frontiers in Medicine Symposium investigators discussed the genetic, physiological, nutritional, and pharmacological mechanisms involved in the regulation of plasma H(e), the association of H(e) with arterial occlusive diseases, and the relationships of H(e) with nitric oxide and haemostasis. High plasma H(e) levels usually can be reversed with vitamin supplements. Whether vitamin supplements will affect the evolution of arterial occlusive diseases needs to be established in prospective, placebo-controlled, randomized, clinical trials.
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PMID:Homocyst(e)ine and arterial occlusive diseases. 798 96

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive sterol storage disease characterized by the accumulation of a bile alcohol, cholestanol, in diverse tissues. The disorder is manifested by extensive nervous system involvement, juvenile cataracts, tendon xanthomas, and premature atherosclerosis and is caused by sterol 27-hydroxylase (EC 1.14.13.15) mutations. Recently, two mutations were shown to cause CTX in four Jewish families of Moroccan origin. An additional mutant allele, found in a Jewish family of Algerian origin is characterized here. Sequence analysis revealed a C to T transition at cDNA position 1037 which predicted a threonine to methionine substitution at residue 306 (designated T306M). It is highly suggestive, but not definitive, that this transition is the mutation causing CTX in this family. A search for additional cases from Jewish families of North African extraction identified five new families including 10 cases. The three sterol 27-hydroxylase gene mutations account for all 10 CTX families and their presence may suggest the existence of positive selective forces that lead to an increased prevalence of this relatively rare disease in Jews from North Africa.
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PMID:Molecular genetics of cerebrotendinous xanthomatosis in Jews of north African origin. 801 82

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

Individuals with hepatic lipase (HL) deficiency are often characterized by elevated levels of triglycerides and cholesterol and may be subject to premature atherosclerosis. Missense mutations in the HL gene have been identified in two affected families: substitutions of serine for phenylalanine at amino acid 267 and threonine for methionine at amino acid 383 (S267F and T383M, respectively). To confirm the role of S267F and T383M, respectively). To confirm the role of mutations separately into human HL cDNA by site-directed mutagenesis, and the resulting constructs were independently expressed in COS cells. HL activity and mass were measured and compared with wild-type HL transfectants to determine the effect of these mutations on lipase activity and secretion. Although similar amounts of HL protein were detected intracellularly after transfection with the wild-type and mutant constructs, S267F and T383M HL activity levels were markedly decreased: in S267F, no HL activity was detected, and activity levels in T383M were 38% of wild-type HL. Heparin-induced secretion of the two HL mutants was also severely affected: no detectable activity could be measured in the media of S267F, although some inactive mass (12% of wild-type HL) was secreted; mutant T383M secreted 4% and 20% of wild-type activity and mass, respectively. These results indicate that the single amino acid substitution present in HL S267F is sufficient to render the enzyme completely nonfunctional; in contrast, the T383M mutant retains partial activity but is poorly secreted. Thus, these defects appear capable of accounting for the HL-deficient phenotypes exhibited by individuals carrying the T383M and S267F mutations.
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PMID:Molecular characterization of human hepatic lipase deficiency. In vitro expression of two naturally occurring mutations. 812 42

Interest in total plasma homocysteine (homocyst[e]ine) as a risk factor for atherosclerosis is expanding. However, the origin of plasma homocyst(e)ine has not been defined. Our studies examined the metabolism of homocyst(e)ine by blood cells as a potential contributor to the homeostasis of homocyst(e)inemia. Incubation of blood for 24 hours at 37 degrees C produced a threefold increase in the level of plasma homocyst(e)ine. In samples of fractionated blood cells incubated in vitro, increases in total plasma homocysteine were limited to incubated erythrocyte fractions and were influenced by addition of methionine. Anticoagulants had no significant effect. Incubation of blood in the presence of methionine tagged with sulfur 35 demonstrated incorporation of label into homocysteine and transsulfuration products. Similar incubations of blood cell fractions suggested that synthesis of homocysteine occurred in erythrocytes, whereas leukocytes both synthesized and transsulfurated homocysteine. These findings demonstrated a possible interaction of different blood cells in the metabolism of methionine, as well as their potential role as a source of total plasma homocysteine in plasma.
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PMID:Synthesis and transsulfuration of homocysteine in blood. 813 55

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

Mesangial cell (MC) hyperplasia and accumulation of extracellular matrix are hallmarks of chronic glomerular disease. The present in vitro study examined the effects of cell density on growth, extracellular matrix formation, and protein synthesis of cultured rat MCs. A negative linear relationship was found between initial plating density and DNA synthesis per cell after 24 hours incubation in medium with 10% fetal calf serum (range: 1 x 10(3) to 7 x 10(5) MCs/2cm2, r = 0.996, P < 0.001). Enzyme-linked immunosorbent assay of the amount of fibronectin in the conditioned medium after 72 hours showed a negative relationship with increasing cell density. In contrast, the amount of cell-associated fibronectin increased to maximal values in confluent cultures, and no further increase was seen at supraconfluency. The relative collagen synthesis in the conditioned medium and cell layer--assessed by collagenase digestion after 5 hours [3H]proline pulse labeling--showed a similar pattern. Secreted collagen decreased with increasing cell density from 3.4% to 0.2% of total protein synthesis. In contrast, cell-associated collagen increased from 1.1% to 11.8% of newly synthesized protein until confluency followed by a decrease to 4.2% at supraconfluency. Specific immunoprecipitation of collagen types I, III, and IV revealed a significant (twofold) increase in collagen I synthesis per cell at confluency. Collagen III and IV synthesis was not affected by cell density. Specific protein expression in both the medium and cell layer were analyzed by two-dimensional polyacrylamide gel electrophoresis (150 to 20 kd, pI 5.0 to 7.0) after 20 hours steady-state metabolic labeling with [35S]methionine. Supraconfluent MCs displayed overexpression of 10, underexpression of four, new expression of five, and changed mobility of three different intracellular proteins. Of interest was the overexpression of two proteins (89 kd, pI 5.31 and 72 kd, pI 5.32) that were identified by immunoblotting as the stress proteins heat-shock protein 90 and glucose-related protein 78, respectively. The progressive increase of cell-associated fibronectin and collagens, particularly collagen type I, in confluent MCs resembles extracellular matrix accumulation in glomerular disease. The increased expression of stress proteins in supraconfluent MCs is of interest in view of the analogy between glomerulosclerosis and atherosclerosis in which stress proteins are expressed in high concentrations.
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PMID:Cell density modulates growth, extracellular matrix, and protein synthesis of cultured rat mesangial cells. 821 12

Free radical-induced injury to the arterial wall has been implicated in the pathogenesis and progression of atherosclerosis. To model the in vitro effects of free radicals on endothelial cell function, protein and lipid synthesis were measured after exposing cells to a superoxide generating system of xanthine (X = 100 microM) and xanthine oxidase (XO = 0.2 units). Total protein synthesis, measured by [35S]methionine uptake, decreased by 87.65 +/- 2.04% over 4 hr compared to controls (P < 0.05). Examination of lipid synthesis by high-performance liquid chromatography in cells prelabeled with either [3H]oleic acid or [3H]sodium acetate revealed alterations in all lipid classes. Phospholipid and neutral glyceride synthesis significantly decreased in a time- and dose-dependent fashion compared to controls (two-way ANOVA). In contrast, cholesterol synthesis and lipid peroxidation increased in a time- and dose-dependent fashion. When X = 200 microM and XO = 0.3 units, there was a statistically significant increase in cholesterol synthesis and lipid peroxidation within 24 hr (Tukey's HSD). We conclude that there is evidence of endothelial cell injury as measured by decreases in protein, glyceride, and phospholipid synthesis. The concurrent increases in lipid peroxidation and cholesterol synthesis may explain the relationship between free radical injury and the pathogenesis of atherosclerosis.
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PMID:Free radical-induced alterations in endothelial cell function. 827 66

The atherogenic properties of homocysteine were discovered by observation of arteriosclerosis in children with homocystinuria caused by inherited deficiency of three different enzymes. Hyperhomocysteinemia is generally recognized as an independent risk factor for coronary, cerebral, and peripheral atherosclerosis. Hyperhomocysteinemia is caused by heterozygosity for homocystinuria, micronutrient deficiency from dietary imbalance, toxins, drugs, hormones, and other factors, explaining many key observations concerning the epidemiology of atherosclerosis. The etiological factors for atherosclerosis are believed to increase conversion of methionine to homocysteine thiolactone, the reactive cyclic internal lactone of homocysteine. The free amino groups of low density lipoprotein (LDL) are thiolated by homocysteine thiolactone, causing aggregation and increased uptake of LDL by macrophages, explaining lipid deposition in atheromas. Homocysteine thiolactone, released from homocysteinylated LDL within vascular wall, promotes intimal injury, oxidation of cholesterol and unsaturated lipids, platelet aggregation, thrombogenic factors, myointimal hyperplasia, deposition of sulfated glycosaminoglycans, fibrosis and calcification of atherosclerotic plaques.
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PMID:Chemical pathology of homocysteine. I. Atherogenesis. 829 2


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