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)

Low levels of transgenic mouse apolipoprotein E (apoE) suppress atherosclerosis in apoE knockout (apoE-/-) mice without normalizing plasma cholesterol. To test whether this is due to facilitation of cholesterol efflux from the vessel wall, we produced apoA-I-/-/apoE-/- mice with or without the transgene. Even without apoA-I and HDL, apoA-I-/-/apoE-/- mice had the same amount of aorta cholesteryl ester as apoE-/- mice. Low apoE in the apoA-I-/-/apoE-/- transgenic mice reduced aortic lesions by 70% versus their apoA-I-/-/apoE-/- siblings. To define the free cholesterol (FC) efflux capacity of lipoproteins from the various genotypes, sera were assayed on macrophages expressing ATP-binding cassette transporter A1 (ABCA1). Surprisingly, ABCA1 FC efflux was twice as high to sera from the apoA-I-/-/apoE-/- or apoE-/- mice compared with wild-type mice, and this activity correlated with serum apoA-IV. Immunodepletion of apoA-IV from apoA-I-/-/apoE-/- serum abolished ABCA1 FC efflux, indicating that apoAI-V serves as a potent acceptor for FC efflux via ABCA1. With increasing apoE expression, apoA-IV and FC acceptor capacity decreased, indicating a reciprocal relationship between plasma apoE and apoA-IV. Low plasma apoE (1-3 x 10(-8) M) suppresses atherosclerosis by as yet undefined mechanisms, not dependent on the presence of apoA-I or HDL or an increased capacity of serum acceptors for FC efflux.
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PMID:Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression. 1295 61

Macrophage-specific overexpression of cholesteryl ester hydrolysis in hormone-sensitive lipase transgenic (HSL Tg) female mice paradoxically increases cholesterol esterification and cholesteryl ester accumulation in macrophages, and thus susceptibility to diet-induced atherosclerosis compared to nontransgenic C57BL/6 mice. The current studies suggest that whereas increased cholesterol uptake could contribute to transgenic foam cell formation, there are no differences in cholesterol synthesis and the expression of cholesterol efflux mediators (ABCA1, ABCG1, apoE, PPARgamma, and LXRalpha) compared to wild-type macrophages. HSL Tg macrophages exhibit twofold greater efflux of cholesterol to apoA-I in vitro, suggesting the potential rate-limiting role of cholesteryl ester hydrolysis in efflux. However, macrophage cholesteryl ester levels appear to depend on the relative efficacy of alternate pathways for free cholesterol in either efflux or re-esterification. Thus, increased atherosclerosis in HSL Tg mice appears to be due to the coupling of the efficient re-esterification of excess free cholesterol to its limited removal mediated by the cholesterol acceptors in these mice. The overexpression of cholesterol acceptors in HSL-apoA-IV double-transgenic mice increases plasma HDL levels and decreases diet-induced atherosclerosis compared to HSL Tg mice, with aortic lesions reduced to sizes in nontransgenic littermates. The results in vivo are consistent with the effective efflux from HSL Tg macrophages supplemented with HDL and apoA-I in vitro, and highlight the importance of cholesterol acceptors in inhibiting atherosclerosis caused by imbalances in the cholesteryl ester cycle.
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PMID:Reduced atherosclerosis in hormone-sensitive lipase transgenic mice overexpressing cholesterol acceptors. 1464 95

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disease characterized by elevated serum levels of low-density lipoprotein cholesterol (LDL-C) and ischaemic heart disease early in life. Early diagnosis and treatment are essential to prevent premature atherosclerosis in FH patients. The aim of our study was the evaluation of the effects of genetic [class of the LDL receptor (LDLR) gene mutation, apolipoprotein (apo)E, apoA-IV and cholesterol ester transfer protein gene polymorphisms] and environmental factors (age, sex, smoking habit and body mass index) on the lipid-lowering response to statin therapy in patients with molecularly defined FH. Atorvastatin 20 mg/day was prescribed in 49 patients with heterozygous FH. The lipid profile was examined before and after 12 weeks of therapy. Statin therapy resulted in a decrease of 37% and 36% in LDL-C and apoB levels, respectively. The study population was then divided into 2 groups according to the class of the LDLR mutation [patients sharing a class V mutation (the G1775A mutation, n=21) and patients sharing class II mutations (the G1646A and the C858A mutations, n=28)]. In both groups, the percentage decrement in LDL-C and apoB levels were correlated with the initial LDL-C and apoB levels, respectively. The class of the LDLR mutation affected the LDL-C and apoB-lowering response of heterozygous FH patients to statin therapy. In detail, heterozygotes sharing a class V mutation of the LDLR showed a higher percentage decrement in LDL-C and apoB levels after atorvastatin administration compared to patients sharing class II mutations (49+/-9% versus 34+/-9%, P=0.001 for LDL-C and 42+/-16% versus 35+/-20%, P=0.001 for apoB). The influence of the classes of the LDLR gene mutations on the change of LDL-C and apoB levels to atorvastatin was still significant in a multivariate analysis. None of the other genetic and environmental factors studied affected the lipid-lowering response to atorvastatin therapy in patients with heterozygous FH in a multivariate analysis. Our data indicate that the class of the LDLR gene mutation affects the LDL-C and apoB-lowering response of heterozygous FH patients to statin therapy. Specifically, patients with a class V mutation exhibit higher percentage decrease in LDL-C and apoB levels after statin therapy compared to patients sharing class II mutations.
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PMID:Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia. 1586 14

The extracellular fluid of the intima is rich in lipid-poor species of high density lipoproteins (HDL) that promote efficient efflux of cholesterol from macrophages. Yet, during atherogenesis, cholesterol accumulates in macrophages, and foam cells are formed. We have studied proteolytic modification of HDL by mast cell proteases as a potential mechanism of reduced cholesterol efflux from foam cells. Mast cells are present in human atherosclerotic lesions and, when activated, they expel cytoplasmic granules that are filled with heparin proteoglycans and two neutral proteases, chymase and tryptase. Both proteases were found to specifically deplete in vitro the apoA-I-containing prebeta-migrating HDL (prebeta-HDL) and other lipid-poor HDL particles that contain only apoA-IV or apoE. These losses led to inhibition of the high-affinity component of cholesterol efflux from macrophage foam cells facilitated by the ATP-binding cassette transporter A1 (ABCA1). In contrast, the diffusional component of efflux promoted by alpha-HDL particles was not changed after proteolysis. Mast cell proteases are providing new insights into the role of extracellular proteolysis of HDL as an inhibiting principle of the initial steps of reverse cholesterol transport in the atherosclerotic intima, where many types of protease-secreting cells are present.
Atherosclerosis 2006 Nov
PMID:Mast cell proteases: physiological tools to study functional significance of high density lipoproteins in the initiation of reverse cholesterol transport. 1653 Feb 2

Metabolic syndrome (MetS) is a high-risk condition for premature atherosclerotic vascular disease. Patients with MetS display a lipoprotein profile in which dense low-density lipoproteins (LDL), which are more susceptible to oxidation, predominate. Oxidation of lipoproteins can be attenuated in vivo by enzymatic and nonenzymatic antioxidant defenses, but high-density lipoproteins (HDL) play a key role in the protection of LDL from oxidation. Such activity depends on the presence of apolipoproteins (apoA-I, apoA-II, apoA-IV, apoE) and enzymes (paraoxonase 1, platelet activating factor-acetylhydrolase, lecithin:cholesterol acyltransferase, glutathione peroxidase). The impairment of HDL antioxidative activity in MetS is partly related to an enrichment of small HDL in triglycerides and their depletion in cholesteryl esters, to the replacement of apoA-I by serum amyloid A, and to glycation and oxidation of apoA-I. Therapeutic normalization of the quantity and the quality of HDL particles may constitute a novel approach to attenuate atherosclerosis and cardiovascular risk in MetS.
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PMID:Alterations in lipoprotein defense against oxidative stress in metabolic syndrome. 1704 77

Folic acid is a vitamin that when used as a dietary supplementation can improve endothelial function. To assess the effect of folic acid on the development of atherosclerosis, male apolipoprotein E-deficient mice fed a standard chow diet received either water (control group) or an aqueous solution of folic acid that provided a dose of 75 microg/kg/day, for ten weeks. At the time of sacrifice, blood was drawn and the heart removed. The study measured plasma homocysteine, lipids, lipoproteins, low-density lipoprotein (LDL) oxidation, isoprostane, paraoxonase, and apolipoproteins, and aortic atherosclerotic areas. In folic acid-treated animals, total cholesterol, mainly carried in very low-density and low-density lipoproteins, increased significantly, and homocysteine, HDL cholesterol, paraoxonase, and triglyceride levels did not change significantly. Plasma isoprostane and apolipoprotein (apo) B levels decreased. The resistance of LDL to oxidization and plasma apoA-I and apoA-IV levels increased with a concomitant decrease in the area of atherosclerotic lesions. The administration of folic acid decreased atherosclerotic lesions independently of plasma homocysteine and cholesterol levels, but was associated with plasma levels of apolipoproteins A-I, A-IV and B, and decreased oxidative stress.
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PMID:Folic acid supplementation delays atherosclerotic lesion development in apoE-deficient mice. 1711 6

To test the hypothesis that extra virgin olive oils from different cultivars added to Western diets might behave differently than palm oil in the development of atherosclerosis, apoE-deficient mice were fed diets containing different cultivars of olive oil for 10 weeks. Female mice were assigned randomly to one of the following five groups: (1-4) fed chow diets supplemented with 0.15% (w/w) cholesterol and 20% (w/w) extra virgin olive oil from the Arbequina, Picual, Cornicabra, or Empeltre cultivars, and (5) fed a chow diet supplemented with 0.15% cholesterol and 20% palm oil. Compared to diets containing palm oil, a Western diet supplemented with one of several varieties of extra virgin olive oil decreased atherosclerosis lesions, reduced plaque size, and decreased macrophage recruitment. Unexpectedly, total plasma paraoxonase activity, apoA-I, plasma triglycerides, and cholesterol played minor roles in the regulation of differential aortic lesion development. Extra virgin olive oil induced a cholesterol-poor, apoA-IV-enriched lipoparticle that has enhanced arylesterase and antioxidant activities, which is closely associated with reductions in atherosclerotic lesions. Given the anti-atherogenic properties of extra virgin olive oil evident in animal models fed a Western diet, clinical trials are needed to establish whether these oils are a safe and effective means of treating atherosclerosis.
Atherosclerosis 2007 Oct
PMID:Accelerated atherosclerosis in apolipoprotein E-deficient mice fed Western diets containing palm oil compared with extra virgin olive oils: a role for small, dense high-density lipoproteins. 1714 84

Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon -2, Q[-2]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small alpha-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow alpha migrating apoA-IV- and apoE-containing HDL, while in the eight heterozygotes, there was loss of large alpha-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II alpha-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.
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PMID:Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency. 1799 56

Altered levels of adipokines, derived as a result of distorted adipocytes, are the major factors responsible for changing biochemical parameters in obesity that leads to the development of metabolic disorders such as insulin resistance and atherosclerosis. In our previous reports, chitosan oligosaccharides (CO) were proved to inhibit the differentiation of 3T3-L1 adipocytes. In the present study, an attempt was made to investigate the anti-obesity and anti-diabetic effect of CO on ob/ob mice, by means of differential proteomic analysis of plasma. This was followed by immunoblotting, and gene expression in adipose tissue to clarify the molecular mechanism. CO treatment showed reduced diet intake (13%), body weight gain (12%), lipid (29%) and glucose levels (35%). 2-DE results showed differential levels of five proteins namely RBP4, apoE, and apoA-IV by >2-fold down-regulation and by >2-fold of apoA-I and glutathione peroxidase (GPx) up-regulation after CO treatment. Immunoblotting studies of adiponectin and resistin showed amelioration in their levels in plasma. Furthermore, the results of gene expressions for adipose tissue specific TNF-alpha, and IL-6 secretary molecules were also down-regulated by CO treatment. Gene expressions of PPAR gamma in adipose tissue were in good agreement with the ameliorated levels of adipokines, thereby improving the pathological state. Taken together, CO might act as a potent down-regulator of obesity-related gene expression in ob/ob mice that may normalize altered plasma proteins to overcome metabolic disorders of obesity.
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PMID:Plasma proteome analysis for anti-obesity and anti-diabetic potentials of chitosan oligosaccharides in ob/ob mice. 1929 49

We addressed how advanced glycation (AGE) affects the ability of apoA-IV to impair inflammation and restore the expression of genes involved in cholesterol efflux in lipopolysaccharide- (LPS-) treated macrophages. Recombinant human apoA-IV was nonenzymatically glycated by incubation with glycolaldehyde (GAD), incubated with cholesterol-loaded bone marrow-derived macrophages (BMDMs), and then stimulated with LPS prior to measurement of proinflammatory cytokines by ELISA. Genes involved in cholesterol efflux were quantified by RT-qPCR, and cholesterol efflux was measured by liquid scintillation counting. Carboxymethyllysine (CML) and pyrraline (PYR) levels, determined by Liquid Chromatography-Mass Spectrometry (LC-MS/MS), were greater in AGE-modified apoA-IV (AGE-apoA-IV) compared to unmodified-apoA-IV. AGE-apoA-IV inhibited expression of interleukin 6 (Il6), TNF-alpha (Tnf), IL-1 beta (Il1b), toll-like receptor 4 (Tlr4), tumor necrosis factor receptor-associated factor 6 (Traf6), Janus kinase 2/signal transducer and activator of transcription 3 (Jak2/Stat3), nuclear factor kappa B (Nfkb), and AGE receptor 1 (Ddost) as well as IL-6 and TNF-alpha secretion. AGE-apoA-IV alone did not change cholesterol efflux or ABCA-1 levels but was unable to restore the LPS-induced reduction in expression of Abca1 and Abcg1. AGE-apoA-IV inhibited inflammation but lost its ability to counteract the LPS-induced changes in expression of genes involved in macrophage cholesterol efflux that may contribute to atherosclerosis.
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PMID:Advanced Glycated apoA-IV Loses Its Ability to Prevent the LPS-Induced Reduction in Cholesterol Efflux-Related Gene Expression in Macrophages. 3241 Aug 61


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