Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been postulated that an accumulation of a sulfhydryl-containing amino acid, homocysteine in plasma may induce arteriosclerosis. In order to explore a possible contribution of homocysteine to the development of cerebral infarction in middle-aged and elderly patients, plasma sulfhydryl-containing amino acid profiles of 45 patients with cerebral infarction (CI) were compared with those of 45 normotensive and 45 hypertensive controls, and 20 patients with cerebral bleeding (CB), of similar ages and sex. The concentrations of both free and total homocysteine in plasma were highest in patients with CI among the 4 groups, while plasma free and total cysteinylglycine levels were similar. Although both free and total cysteine levels were also higher in patients with CI than in normotensive controls, the total homocysteine/total cysteine ratio was highest in patients with CI among the four groups. The hypertensive controls had higher plasma free and total concentrations than normotensive controls, but the levels did not differ between the 21 normotensive and 24 hypertensive CI patients. Our results suggest that high levels of plasma homocysteine in conjunction with hypertension could be one of the risk factors for arteriosclerotic CI.
Atherosclerosis 1989 Oct
PMID:Plasma sulfhydryl-containing amino acids in patients with cerebral infarction and in hypertensive subjects. 259 23

The complete amino acid sequence of the liver-synthesized apolipoprotein B (apoB) species, apoB 100, has been derived from cloned cDNA. The protein consists of 4536 amino acids (+ a 27 amino acid signal sequence). Cysteine is clustered in the N-terminal 1/10 of the protein, suggesting the presence of a stabilized tertiary structure in this part of the molecule. Three types of structure are suggested to be of importance for the binding of the protein to lipids; (i) hydrophobic sequences with a high probability for beta-sheet structure, (ii) strict amphipathic beta-sheets, and (iii) amphipathic alfa-helices. An apoB 100 molecule is completed within 10-14 min and secreted after approximately 30 min, 1/3 of which is due to the transfer through the endoplasmic reticulum (ER), while 2/3 is spent in the Golgi apparatus. ApoB 100 is co-translationally N-glycosylated and 25% of the oligosaccharide chains is processed in the Golgi compartment. Other posttranslational modifications that have been discussed include covalent acylation and phosphorylation. It has also been suggested that the lipid moiety of the apoB 100 lipoproteins are modified during the passage through the Golgi apparatus. The site of lipoprotein assembly is suggested to be separated from the site of apoB 100 synthesis, and apoB 100 appears to be co-translationally bound to the ER membrane and from this transferred to the ER lumen. Based on these observations a model for the assembly of apoB 100 lipoproteins is discussed in this paper. The intestinal derived apoB species, apoB 48, has a molecular mass of 210 kDa and appears to correspond to the N-terminal 48% of apoB 100. The mechanism by which apoB 48 is formed is still not known. Available data indicate that the protein is formed within the intestinal cells, these data also argue against the possibility that apoB 48 is formed by posttranslational proteolysis of apoB 100. The formation of a separate apoB 48 mRNA by alternative splicing has been suggested, based on the observation of a 7 kb mRNA which corresponds to the 5' portion of the apoB 100 mRNA. However, the most abundant apoB mRNA species found in the intestine have a size that corresponds to that of the apoB 100 mRNA, furthermore the observation that apoB 48 appears to terminate in a 7.5 kb exon that appears to lack alternative splice sites, does not favour the possibility of alternative splicing.
Atherosclerosis 1987 Nov
PMID:Apolipoprotein B: structure, biosynthesis and role in the lipoprotein assembly process. 331 51

We have determined the complete sequence of apolipoprotein (apo) B-100 cDNA. It is 14.1 kilobases in length and codes for a 4563-amino acid protein, including a 27-amino acid signal peptide and a 4536-amino acid mature protein. Further, we identified 2366 residues of apoB-100 by direct sequence analysis of apoB-100 tryptic peptides. The mature peptide is characterized by high hydrophobicity (0.916 kcal/residue) and predicted beta-sheet content (21%). Dot matrix analysis revealed the presence of many long internal repeats in apoB-100. The mature peptide contains 25 cysteine residues, 12 of which are in the N-terminal 500 residues. Twenty potential N-linked glycosylation sites were identified, of which 13 were proven to be glycosylated, and 4 were found not to be glycosylated by direct analysis of tryptic peptides. Our findings on apoB structure provide a basis for future experimentation on the role of apoB-100-containing lipoproteins in atherosclerosis.
 ...
PMID:The complete cDNA and amino acid sequence of human apolipoprotein B-100. 375 43

The early onset of atherosclerotic lesions in homocystinuric individuals has implicated homocyst(e)ine in the development of atherosclerosis. Two trials were conducted in which diets totally or partially deficient in vitamin B-6 were fed to pigs to investigate the accumulation of homocyst(e)ine in the plasma and the development of vascular lesions. In one trial plasma free homocyst(e)ine levels were 179 and 43 mumol/liter in deficient and adequate pigs, respectively, on day 24, while cysteine levels were 39 and 155 mumol/liter. The concentration of plasma protein-bound homocysteine and cysteine reflected the plasma-free values. Because pigs deficient in pyridoxine could be used only over short time intervals, pigs in trial 2 received 0, 0.03, 0.3 or 3 mg (i.e., 0, 2, 20 or 200% of allowance) of supplemental pyridoxine . HCl per kilogram diet. After 12 weeks pigs deficient and adequate in vitamin B-6 were injected intravenously with Evan's blue dye and the vascular trunk perfused with 2% glutaraldehyde. The aorta and major organs were removed and examined for vascular lesions. Grossly no significant lesions were seen. Light microscopy revealed occasional foci of intimal degeneration and mural thickening in the renal arterioles of pigs deficient in vitamin B-6. An area of focal medial necrosis was observed in one of the pigs deficient in vitamin B-6. Pigs fed diets containing 0.03 mg pyridoxine . HCl per kilogram diet had homocyst(e)ine concentrations not different from pigs fed diets with no added pyridoxine. Animals fed diets containing 0.3 mg pyridoxine . HCl per kilogram had homocyst(e)ine concentrations slightly higher than controls fed 3.0 mg/kg. Feed intake and weight gain increased with increasing pyridoxine in the diet. Swine offer an excellent vascular model for humans. Diets partially deficient in vitamin B-6 which cause the homocyst(e)ine concentration to increase, but allow better growth and feed consumption than diets totally deficient in pyridoxine, could be fed to pigs to study homocyst(e)ine-induced vascular damage over extended period of time.
 ...
PMID:Homocyst(e)ine accumulation in pigs fed diets deficient in vitamin B-6: relationship to atherosclerosis. 661 81

Precocious atherosclerosis occurs in homocystinuria due to cystathionine beta-synthase deficiency and there is evidence that homocysteine may produce endothelial damage. Mild homocysteinemia has been reported in heterozygotes after methionine loads and it has been suggested that they could have an increased risk of atherogenesis. We measured plasma amino acids before and after a methionine load (100 mg per kg) in 17 obligatory heterozygotes, in 20 men under 50 yr with established ischemic heart disease, and in matched controls, to determine whether methionine loading allows identification of heterozygotes, and whether there is an altered rate of methionine metabolism in patients with premature coronary artery disease. The obligate heterozygotes had higher mean plasma concentrations of methionine and total homocysteine at 4, 8 and 12 hours after the load than their controls, and lower concentrations of total cysteine and taurine in fasting and all post load samples; however, there was considerable overlap of measurements in heterozygotes and their controls even when differential weightings were applied. There were no differences in mean plasma concentrations of methionine, total homocysteine or total cysteine between the patients with ischemic heart disease and their controls at any measurement point. However, two patients with premature coronary artery disease, identical twins, had persistent elevation of total plasma homocysteine and an exaggerated homocysteine response to methionine. Oral folate restored homocysteine concentrations before and after methionine to normal.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria. 668 24

Intimal thickening in arteries is considered a site of predilection for atherosclerosis. We investigated whether oral application of the nitric oxide (NO) donors SPM-5185 [N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethylester, 10 mg/kg body weight twice daily (b.i.d.)] and molsidomine (10 mg/kg body weight/day) can retard neointima formation and changes in vascular reactivity induced by a nonocclusive, soft silicone collar positioned around the left carotid artery of rabbits. The contralateral carotid artery was sham operated and served as a control. Drug and placebo (diet without drug) treatments were initiated 7 days before placement of the collar. At the end of the experiments, two segments were cut from each collared and sham-treated artery, one for measurement of the cross-sectional area of intima and media and the other for isometric tension recording. Sham treatment did not result in intimal thickening in either group. In contrast, the intima/media (I/M) ratio was considerably increased after 14 days of collar treatment as a result of neointima formation. Intimal thickening was significantly inhibited by SPM-5185 (I/M ratio 0.05 +/- 0.01 vs. 0.11 +/- 0.02, p < 0.05), but not by molsidomine (0.06 +/- 0.02 vs. 0.08 +/- 0.02, p = 0.49), which is a donor of both NO and superoxide anions. Neither collar nor NO donor treatment altered the area of the media. SPM-5185 did not alter the percentage of replicating smooth muscle cells (SMC) in the media after collar treatment, as demonstrated by their immunoreactivity for proliferating cell nuclear antigen (PCNA).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effect of nitric oxide donors on neointima formation and vascular reactivity in the collared carotid artery of rabbits. 747 52

The so-called very low density lipoprotein receptors (VLDLRs) are related to the LDLR gene family. So far, naturally occurring mutations have only been described for the prototype LDLR; in humans, they cause familial hypercholesterolemia. Here we describe a naturally occurring mutation in a VLDLR that causes a dramatic abnormal phenotype. Hens of the mutant restricted-ovulator chicken strain carry a single mutation, lack functional oocyte receptors, are sterile, and display severe hyperlipidemia with associated premature atherosclerosis. The mutation converts a cysteine residue into a serine, resulting in an unpaired cysteine and greatly reduced expression of the mutant avian VLDLR on the oocyte surface. Extraoocytic cells in the mutant produce higher than normal amounts of a differentially spliced form of the receptor that is characteristic for somatic cells but absent from germ cells.
 ...
PMID:Mutant oocytic low density lipoprotein receptor gene family member causes atherosclerosis and female sterility. 756 42

This study shows that the intracellular concentration of homocysteine in cultured cells is kept low due to an accumulation in the medium. The intracellular level of homocysteine was decreased when its precursor, methionine, was omitted from the culture medium. Intracellular glutathione and cysteine were lowered in cystine-deficient medium. Intracellular glutathione was also lowered when copper ions were added to the culture medium. It is evident from this study that the intracellular concentration of homocysteine was not influenced by the lowered level of glutathione and/or cysteine. High amounts of homocysteine added to the medium give rise to an increase of intracellular reduced homocysteine, which participates in the transsulfuration pathway and can replace cysteine in the synthesis of glutathione. The addition of relatively high amounts of reduced homocysteine (500 mumol/l) in the presence of copper ions (100 mumol/l) to the culture medium can be directly toxic to the cells, possibly due to oxygen radicals formed by thiol auto-oxidation. Whilst the level of homocysteine in this study using short-time cell culture experiment is much higher than the mild hyperhomocysteinemia thought to be atherogenic in humans, it is conceivable that over a longer time course these levels of homocysteine could be sufficient to induce endothelial dysfunction, eventually leading to atherosclerosis.
 ...
PMID:Metabolism of homocysteine, its relation to the other cellular thiols and its mechanism of cell damage in a cell culture line (human histiocytic cell line U-937). 757 72

The low-density lipoprotein (LDL) receptor plays a central role in mammalian cholesterol metabolism, clearing lipoproteins which bear apolipoproteins E and B-100 from plasma. Mutations in this molecule are associated with familial hypercholesterolemia, a condition which leads to an elevated plasma cholesterol concentration and accelerated atherosclerosis. The N-terminal segment of the LDL receptor contains a heptad of cysteine-rich repeats that bind the lipoproteins. Similar repeats are present in related receptors, including the very low-density lipoprotein receptor and the LDL receptor-related protein/alpha 2-macroglobulin receptor, and in proteins which are functionally unrelated, such as the C9 component of complement. The first repeat of the human LDL receptor has been expressed in Escherichia coli as a glutathione S-transferase fusion protein, and the cleaved and purified receptor module has been shown to fold to a single, fully oxidized form that is recognized by the monoclonal antibody IgG-C7 in the presence of calcium ions. The three-dimensional structure of this module has been determined by two-dimensional NMR spectroscopy and shown to consist of a beta-hairpin structure, followed by a series of beta turns. Many of the side chains of the acidic residues, including the highly conserved Ser-Asp-Glu triad, are clustered on one face of the module. To our knowledge, this structure has not previously been described in any other protein and may represent a structural paradigm both for the other modules in the LDL receptor and for the homologous domains of several other proteins. Calcium ions had only minor effects on the CD spectrum and no effect on the 1H NMR spectrum of the repeat, suggesting that they induce no significant conformational change.
 ...
PMID:Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. 760 91

Cigarette smoking is associated with an increased risk of premature atherosclerosis. The underlying mechanisms responsible for this association are unknown. Recent work from this laboratory has shown that ex vivo exposure to plasma to gas-phase cigarette smoke (CS) produces a rapid inhibition of lecithin-cholesterol acyltransferase (LCAT) activity and crosslinking of HDL-apolipoproteins. The goal of the present study was to investigate the mechanism(s) by which CS inhibited LCAT and modified HDL. When dialyzed human plasma (12 ml) was exposed to the gas-phase of an equivalent of 1/8 of a cigarette (one 'puff') at 15 min intervals for 3 h, LCAT activity was reduced by 76 +/- 1% compared to controls; supplementation of plasma with glutathione produced a dose-dependent protection of LCAT activity where at the highest concentration (1 mM) 78% protection was observed. A similar protection was obtained with N-acetyl cysteine (1 mM). In addition to LCAT inhibition, HDL-apolipoproteins were crosslinked after 3 h exposure of plasma to CS; crosslinking was reduced by the addition of either glutathione or N-acetyl cysteine to plasma. The amino compounds N-acetyl lysine, N-acetyl arginine, and aminoguanidine failed to protect LCAT and HDL indicating a specificity with regard to the ability of free thiols to buffer the deleterious components of CS which inhibited LCAT and crosslinked HDL-apolipoproteins. Since LCAT contains two free cysteine residues (Cys-31 and -184) near the active site of the enzyme, we tested whether pretreatment of plasma with the reversible sulfhydryl modifying compound, 5,5'-dithiobis-2-nitrobenzoic acid (DTNB), could protect LCAT from CS-induced inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Gas-phase cigarette smoke inhibits plasma lecithin-cholesterol acyltransferase activity by modification of the enzyme's free thiols. 765 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>