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)

Remnant-like particle (RLP) lipid and apolipoprotein (apo) levels were determined in the plasma of normolipidemic and hyperlipidemic subjects, in order to investigate the relationship between RLP levels and the concentration of other plasma lipoprotein parameters. Plasma RLP fractions were isolated with the use of an immunoaffinity gel (RLP-Cholesterol Jimro II, Japan Immunoresearch Lab.), containing specific anti-apoB-100 and anti-apoA-I antibodies. Four groups of human subjects were selected, who had either matching or significantly different levels of plasma triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C): (1) normolipidemic control (NC) subjects (n = 10), (2) patients with elevated levels of LDL-C (type IIa, LDL-C (mean +/- S.E.), 4.65 +/- 0.09 mmol/l, n = 10), (3) hypertriglyceridemic (HTG) patients with elevated LDL-C (type IIb, TG: 3.86 +/- 0.36; LDL-C: 4.67 +/- 0.21 mmol/l, n = 10), and (4) HTG patients with normal LDL-C (type IV, TG: 3.71 +/- 0.39 mmol/l, n = 10). NC subjects (RLP-C: 0.22 +/- 0.01; RLP-TG: 0.24 +/- 0.03 mmol/l) had RLP apoB, apoC-III and apoE levels of 3.2 +/- 0.3, 1.8 +/- 0.3, and 1.4 +/- 0.1 mg/dl, representing 3.2 +/- 0.4, 14.5 +/- 1.4 and 32.1 +/- 2.1% of total plasma levels, respectively. RLP lipid and apolipoprotein concentrations were significantly higher in HTG groups (type IIb and IV) compared to NTG groups (NC and type IIa) (e.g. RLP-C: 0.50 +/- 0.07 and 0.58 +/- 0.11 vs. 0.22 +/- 0.01 and 0.21 +/- 0.01 mmol/l, respectively (P < 0.01); RLP apoB: 8.4 +/- 1.6 and 8.2 +/- 0.9 vs. 3.2 +/- 0.3 and 3.4 +/- 0.2 mg/dl, respectively (P < 0.01)). No significant difference in RLP levels was observed between groups having different LDL levels, and thus no correlation existed between RLP-C and LDL-C levels (r = 0.24, n.s.). RLP-C and RLP apoB levels were, however, correlated with VLDL-C and VLDL apoB (r = 0.86, P < 0.001 and r = 0.70, P < 0.001, respectively). These results demonstrate that elevated levels of both RLP lipids and apolipoproteins are characteristic of patients with increased levels of plasma triglyceride, and not patients with increased levels of LDL.
Atherosclerosis 1998 Jul
PMID:Plasma remnant-like particle lipid and apolipoprotein levels in normolipidemic and hyperlipidemic subjects. 969 4

Mutations in the low density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia, a human disease characterized by premature atherosclerosis and markedly elevated plasma levels of LDL cholesterol and apolipoprotein (apo) B100. In contrast, mice deficient for the LDL receptor (Ldlr-/-) have only mildly elevated LDL cholesterol levels and little atherosclerosis. This difference results from extensive editing of the hepatic apoB mRNA in the mouse, which limits apoB100 synthesis in favor of apoB48 synthesis. We have generated Ldlr-/- mice that cannot edit the apoB mRNA and therefore synthesize exclusively apoB100. These mice had markedly elevated LDL cholesterol and apoB100 levels and developed extensive atherosclerosis on a chow diet. This authentic model of human familial hypercholesterolemia will provide a new tool for studying atherosclerosis.
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PMID:A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet. 970 Dec 40

Two population samples in western Sicily, one rural and one urban, were studied to evaluate the influence of dietary habits on cardiovascular risk factors. One hundred and fifty-five rural subjects (73 males, 82 females) and 155 age- and sex-matched urban subjects (71 males, 84 females) were enrolled. All subjects related their personal and familial history, physical activity levels, and had a complete physical and instrumental examination. Blood was collected after an overnight fast, without stasis. The following parameters were measured: blood glucose, total cholesterol, HDL-cholesterol, triglycerides, apolipoproteins A1 and B100, fibrinogen, factors VII and VIII, tissue plasminogen activator, plasminogen activator inhibitor, and plasminogen. Dietary habits were recorded on two occasions by means of a week diary (7-day food record). The rural sample followed the so-called "Mediterranean diet", while the urban sample followed a diet with significantly higher cholesterol and fat (in particular saturated fatty acids) intake and a significantly lower fiber intake. Both males and females in the rural population had significantly lower total cholesterol and apolipoprotein B100 levels than those in the urban sample, although rural males had significantly higher HDL-cholesterol levels. Both males and females in the rural sample had significantly lower factor VII and plasminogen activator inhibitor levels, although rural males had lower tissue plasminogen activator and fibrinogen levels than their urban counterparts. The positive effects of the "Mediterranean diet" on lipid, coagulation and fibrinolytic parameters which play a key role in the pathogenesis of atherosclerosis indicate that this dietary pattern should be adopted by the entire population.
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PMID:[Food habits and cardiovascular risk factors in 2 population samples of western Sicily]. 977 75

Hypobetalipoproteinemia (HBLP) is characterized by plasma concentrations of apolipoprotein B (apoB) and low density lipoprotein cholesterol (LDL-C) below the fifth percentile. Some forms of HBLP have been shown to be due to truncated forms of apoB-100. A total of 3873 subjects participating in the Framingham Offspring Study had LDL-C levels measured every 4 to 5 years throughout a 25-year period. Seventy-five subjects were identified with persistent HBLP, defined as an LDL-C <70 mg/dL on at least 2 observations, for a prevalence of 1.9% in this population. Compared with subjects with LDL- C >/=70 mg/dL, subjects with HBLP had significantly lower mean levels of total cholesterol, LDL-C, triglyceride, and apoB; higher levels of high density lipoprotein cholesterol; and a higher prevalence of the E2/E3 genotype: 38.7% versus 10.9% (P<0.001). Men with HBLP had a larger mean LDL particle size than did men with an LDL- C >/=70 mg/dL. One individual had a truncated apoB as a cause of HBLP, for a prevalence of 0.03%. Medical causes of HBLP included 2 cases of Crohn's disease, 1 of hemochromatosis, and 1 of hepatitis. Three subjects with HBLP developed coronary heart disease, for an incidence of 4% compared with 5% in those with an LDL- C >/=70 mg/dL (P=NS). The incidence of cancer was 8% in those with HBLP compared with 4% in those with an LDL-C >/=70 mg/dL (P=0.21). In conclusion, a truncated apoB was a rare cause of HBLP, whereas the E2/E3 genotype was a much more common cause. A large prospective study is needed to evaluate the incidence of cancer and atherosclerosis in subjects with HBLP.
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PMID:Frequency of ApoB and ApoE gene mutations as causes of hypobetalipoproteinemia in the framingham offspring population. 981 13

Lipoprotein(a) [Lp(a)] is one important cause of atherosclerosis. It consists of one molecule of low density lipoprotein and an additional molecule of apo(a) linked to apoB-100 by a disulfide bridge. Apo(a)s are partially homologous to plasminogen, with one kringle 5 and 10-40 repeats of kringle 4. As there is no drug therapy available, we treated three patients who had suffered from at least one myocardial infarction and had Lp(a) as the only risk factor for atherosclerosis. Since October 1992, 186 immunoadsorption treatments have been carried out weekly with Sepharose-coupled anti-Lp(a)-columns. To achieve a reduction in Lp(a) from 78-250 mg/dL before apheresis to below 25 mg/dL immediately after apheresis, patient plasma volume had to be treated two to three times. Treatments lasted 3-5 h. Immediately reversible side-effects such as flushing and tachycardia during the first treatment were seen in 9% of immunoadsorptions. Non-specific protein loss remained tolerable, if one takes into account that the patients received approximately 1 L of ACDB with heparin as anticoagulant and some of the column-rinsing buffer. One patient's clinical condition and exercise test improved dramatically as did coronary angiography after 2 years. Another patient had no change after 1 year, the third patient showed subjective improvement and has not yet had repeat angiography after 1 year of treatment. We conclude that Lp(a)-apheresis may retard progression of atherosclerosis in patients with selective Lp(a) elevation. Further studies to support this hypothesis are needed.
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PMID:Lipoprotein(a)-apheresis in the secondary prevention of coronary heart disease. 1016 48

Oxidative modification of LDL may be important in the initiation and/or progression of atherosclerosis, but the precise mechanisms through which low density lipoprotein (LDL) is oxidized are unknown. Recently, evidence for the existence of HOCl-oxidized LDL in human atherosclerotic lesions has been reported, and myeloperoxidase (MPO), which is thought to act through production of HOCl, has been identified in human atherosclerotic lesions. In the present report we describe the formation of 2,4-dinitrophenylhydrazine (DNPH)-reactive modifications in the apolipoprotein (apo) by exposure of LDL to myeloperoxidase in vitro. In contrast with the complex mixture of peptides from oxidation of LDL with reagent HOCl, oxidation with MPO in vitro produced a major tryptic peptide showing absorbance at 365 nm. This peptide was isolated and characterized as VELEVPQL(*C)SFILK..., corresponding to amino acid residues 53-66...on apoB-100. Mass spectrometric analyses of two tryptic peptides from oxidation of LDL by HOCl indicated formation of the corresponding methionine sulfoxide (M=O), cysteinyl azo (*C), RS -N= N-DNP, derivatives of EEL(*C)T(M=O)FIR and LNDLNS VLV(M=O)PTFHVPFTDLQVPS(*C)K, which suggest oxidation to the corresponding sulfinic acids (RSO2H) by HOCl. The present results demonstrate that DNPH-reactive modifications other than aldehydes and ketones can be formed in the oxidation of proteins and illustrate how characterization of specific products of protein oxidation can be useful in assessing the relative contributions of different and unexpected mechanisms to the oxidation of LDL and other target substrates. The data also suggest a direct interaction of the LDL particle with the active site on myeloperoxidase and indicate that effects of the protein microenvironment can greatly influence product formation and stability.
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PMID:Selective modification of apoB-100 in the oxidation of low density lipoproteins by myeloperoxidase in vitro. 1019 Dec 93

Oxidized LDL is implicated in atherosclerosis; however, the pathways that convert LDL into an atherogenic form in vivo are not established. Production of reactive nitrogen species may be one important pathway, since LDL recovered from human atherosclerotic aorta is enriched in nitrotyrosine. We now report that reactive nitrogen species generated by the MPO-H2O2-NO2- system of monocytes convert LDL into a form (NO2-LDL) that is avidly taken up and degraded by macrophages, leading to massive cholesterol deposition and foam cell formation, essential steps in lesion development. Incubation of LDL with isolated MPO, an H2O2-generating system, and nitrite (NO2-)-- a major end-product of NO metabolism--resulted in nitration of apolipoprotein B 100 tyrosyl residues and initiation of LDL lipid peroxidation. The time course of LDL protein nitration and lipid peroxidation paralleled the acquisition of high-affinity, concentration-dependent, and saturable binding of NO2-LDL to human monocyte-derived macrophages and mouse peritoneal macrophages. LDL modification and conversion into a high-uptake form occurred in the absence of free metal ions, required NO2-, occurred at physiological levels of Cl-, and was inhibited by heme poisons, catalase, and BHT. Macrophage binding of NO2-LDL was specific and mediated by neither the LDL receptor nor the scavenger receptor class A type I. Exposure of macrophages to NO2-LDL promoted cholesteryl ester synthesis, intracellular cholesterol and cholesteryl ester accumulation, and foam cell formation. Collectively, these results identify MPO-generated reactive nitrogen species as a physiologically plausible pathway for converting LDL into an atherogenic form.
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PMID:Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. 1035 64

Lifibrol (4-(4'-tert-butylphenyl)-1-(4'carboxyphenoxy)-2-butanol), a new hypocholesterolemic drug, effectively reduces total cholesterol (CH), low density lipoprotein (LDL)-CH, and apolipoprotein (apo) B in experimental animals and in humans. The impact of Lifibrol on the metabolism of apoB-100 containing lipoproteins in patients with hyperlipoproteinemia using endogenous labeling with stable isotopes is examined. Kinetic studies were performed in four male hypercholesterolemic individuals (type IIa) before and on treatment with 450 mg of Lifibrol daily for 4 weeks, and in five male individuals suffering from mixed hyperlipidemia (type IIb) before and on therapy for 12 weeks. Kinetic parameters were estimated by multicompartmental modeling. Lifibrol therapy reduced total CH by 16% (P = 0.012) in all patients, increased triglycerides (TG) by 11% (not significant) in type IIa patients and decreased TG by 34% (P = 0.059) in type IIb patients. During Lifibrol therapy, LDL apoB-100 concentrations decreased by 19% (P = 0.011) in all patients. The decrease in LDL apoB concentrations with Lifibrol therapy was due to an overall increase (75%, P = 0.006) of the fractional catabolic rates (FCR) of LDL apoB. This increase was partially attenuated by a 33% increase in LDL apoB production rate (PR) (P = 0.041). The overall production of apoB increased only slightly. Our data suggest that the major mechanism by which Lifibrol lowers LDL-CH is an increase in receptor-mediated catabolism of LDL rather than a decrease in hepatic apoB production.
Atherosclerosis 1999 May
PMID:Lifibrol enhances the low density lipoprotein apolipoprotein B-100 turnover in patients with hypercholesterolemia and mixed hyperlipidemia. 1038 Dec 90

Human blood contains a form of minimally modified low density lipoprotein (LDL), termed LDL-, whose origin remains unknown. Exploring the mechanism of formation, we found that LDL- can be produced in plasma in the absence of oxygen following LDL incubation with oxidized hemoglobin species. A high degree of apolipoprotein B100 modification results from covalent association of hemoglobin with LDL involving dityrosine formation but not due to the malonaldehyde epitope formation. This was evidenced by the cross-reactivity of oxidized LDL with antibodies against hemoglobin that was accompanied by a 60-fold increase in dityrosine levels. In this study we found significantly higher LDL- levels in the blood of hemodialysis patients, perhaps contributing to their greatly increased risk of atherosclerosis. The mechanism of LDL- formation was studied during ex vivo blood circulation using a model system resembling clinical hemodialysis in terms of the induction of inflammatory responses. This circulation increased free hemoglobin and LDL- levels compared with non-circulated blood without appreciable lipid peroxidation. Pronounced increases in LDL- were found also during circulation of plasma supplemented with nanomolar hemoglobin levels. The increase in dityrosine content and presence of heme in LDL after blood circulation suggest that LDL is modified, in part, by hemoglobin-LDL conjugates containing heme. Thus, hemoglobin-mediated reactions leading to LDL oxidation in plasma can account for high LDL- levels in hemodialysis patients.
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PMID:Oxidative cross-linking of ApoB100 and hemoglobin results in low density lipoprotein modification in blood. Relevance to atherogenesis caused by hemodialysis. 1038 89

Intracellular cholesterol biosynthesis may play a key role in supplying cholesterol (as cholesteryl ester) for the neutral core of very low density lipoprotein (VLDL), thus modulating the secretion of apolipoprotein B-100 (apo B-100) from hepatocytes. The effect of compound NK-104 was studied, a new competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-reductase), on apo B-100 synthesis and secretion from the human hepatoma cell line Hep G2. Cells were preincubated with NK-104 (0.01-5 microM) in the presence or absence of oleate (0.8 mM). Apo B-100 in the medium was determined by an enzyme-linked immunosorbent assay (ELISA). Incubation of Hep G2 with NK-104 resulted in a marked inhibition of cholesterogenesis (up to 95%), determined as incorporation of [14C]acetate into sterols, and decreased in a dose-dependent manner apo B-100 secretion, both in basal conditions (from 110 to 82 ng/mg cell protein, P < 0.01) and after incubation with oleate (from 227 to 165 ng/mg cell protein, P < 0.01). Density gradient for distribution of apo B-100 secreted, showed that this decrease was essentially due to a reduction of apo B-100 associated with lipoproteins in the density range of low density lipoproteins (LDL). Pulse chase experiment demonstrated that NK-104 did not affect the synthetic rate of apo B-100 but increased intracellular degradation of newly synthesized protein. The compound had only marginal effect on the mass of intracellular triglyceride but significantly decreased intracellular mass of free cholesterol and cholesteryl ester (P < 0.01). It is speculated that the ability of compound NK-104 to decrease apo B-100 secretion from Hep G2 cells is due to a decreased intracellular cholesterol availability.
Atherosclerosis 1999 Jul
PMID:NK-104, a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, decreases apolipoprotein B-100 secretion from Hep G2 cells. 1042 99


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