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Showing 1421–1440 of 2058 publications.
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Glaros, Elias N.; Kim, Woojin Scott; Wu, Ben Jing; Suarna, Cacang; Quinn, Carmel M.; Rye, Kerry Anne; Stocker, Roland; Jessup, Wendy K.; Garner, BrettGlycosphingolipids (GSL) have been implicated as potential atherogenic lipids. Inhibition of hepatic serine palmitoyl transferase (SPT) reduces plasma sphingomyelin (SM) levels in the absence of changes in cholesterol or triglyceride (TG) concentration and this leads to a reduction of atherosclerosis in apolipoprotein-E gene knockout (apoE-/-) mice. The possibility that the reduced atherosclerosis resulting from SPT inhibition is associated with decreases in plasma GSL concentration has not been examined and was the primary aim of this investigation. We show that intraperitoneal delivery of the SPT inhibitor myriocin for 9 weeks inhibits atherosclerosis in apoE-/- mice fed a high fat diet. Lesion inhibition was most pronounced at the aortic arch and distal sites of the thoracic and abdominal aorta. There was also a trend towards a reduction in lesion area at the aortic root. Myriocin treatment resulted in significant reductions in both plasma SM and GSL concentration of 42% and 25%, as assessed by enzymatic and HPLC methods, respectively. Moreover, SM and GSL concentrations were significantly correlated, indicating that SPT inhibition suppresses the synthesis of both these sphingolipids concomitantly. The inhibition of atherosclerosis induced by myriocin was not associated with changes in plasma cholesterol or TG concentrations or lipoprotein profiles as determined by FPLC. These data indicate that therapeutic reduction of plasma SM and/or GSL concentrations may offer a novel treatment for atherosclerosis. 2006 Elsevier Inc. All rights reserved.
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Barter, Philip J.; McPherson, Y. Ruth; Song, Kjioung S.; Kesaniemi, YrjAntero; Mahley, Robert W.; Waeber, Gard; Bersot, Thomas P.; Mooser, Vincent E.; Waterworth, Dawn M.; Grundy, Scott M.Context: The worldwide epidemic of overweight and obesity is setting the scene for a new wave of premature cardiovascular disease. Objective: The objective of this study was to define relationships between dyslipidemia and other metabolic abnormalities in overweight subjects. Design: This study included comparison of overweight subjects with and without dyslipidemia. Setting: The setting was an institutional practice. Patients: Dyslipidemic subjects (n = 715) had plasma triglyceride greater than or equal to the 75th percentile in combination with high-density lipoprotein cholesterol (HDL-C) less than or equal to the 25th percentile. Unrelated, normolipidemic controls (n = 1073) had HDL-C higher than the median and triglyceride lower than the median. It was a requirement for the control subjects to have a body mass index (BMI) greater than 25 kg/m2. Main Outcome Measures: The main outcome measures included BMI, inflammatory markers, adipokines, blood pressure, and fasting plasma glucose and insulin. Results: The mean BMI in the subjects and controls was 28.7 and 28.2 kg/m2, respectively. Subjects had higher levels of plasma highsensitivity C-reactive protein (3.0 vs. 2.0 mg/liter; P < 0.001), lower levels of adiponectin (4.7 vs. 6.6 mg/liter; P < 0.001), and, after adjustment for age, BMI, gender, smoking, statin, and ?-blocker use, higher systolic (P = 0.001) and diastolic (P = 0.05) blood pressures. Fasting plasma glucose, insulin, and homeostasis model of assessment-insulin resistance were all significantly higher in subjects than controls (P < 0.0001). Conclusions: Identification of people solely on the basis of an elevated plasma triglyceride and a low HDL-C uncovers an overweight group of people who have a generalized metabolic disorder. In contrast, overweight people with normal plasma lipids have normal glucose and insulin metabolism, low levels of inflammatory markers, and normal blood pressure. Such people may thus be at relatively low risk of developing diabetes and cardiovascular disease despite being overweight. Copyright 2007 by The Endocrine Society.
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Kim, Woojin Scott; Rahmanto, Aldwin Suryo; Kamili, Alvin; Rye, Kerry Anne; Guillemin, G. J.; Gelissen, Ingrid C.; Jessup, Wendy K.; Hill, Andrew F.; Garner, BrettMaintenance of an adequate supply of cholesterol is important for neuronal function, whereas excess cholesterol promotes amyloid precursor protein (APP) cleavage generating toxic amyloid-? (A?) peptides. To gain insights into the pathways that regulate neuronal cholesterol level, we investigated the potential for reconstituted apolipoprotein E (apoE) discs, resembling nascent lipoprotein complexes in the central nervous system, to stimulate neuronal [3H]cholesterol efflux. ApoE discs potently accelerated cholesterol efflux from primary human neurons and cell lines. The process was saturable (17.5 ?g of apoE/ml) and was not influenced by APOE genotype. High performance liquid chromatography analysis of cholesterol and cholesterol metabolites effluxed from neurons indicated that <25% of the released cholesterol was modified to polar products (e.g. 24-hydroxycholesterol) that diffuse from neuronal membranes. Thus, most cholesterol (?75%) appeared to be effluxed from neurons in a native state via a transporter pathway. ATP-binding cassette transporters ABCA1, ABCA2, and ABCG1 were detected in neurons and neuroblastoma cell lines and expression of these cDNAs revealed that ABCA1 and ABCG1 stimulated cholesterol efflux to apoE discs. In addition, ABCA1 and ABCG1 expression in Chinese hamster ovary cells that stably express human APP significantly reduced A? generation, whereas ABCA2 did not modulate either cholesterol efflux or A? generation. These data indicate that ABCA1 and ABCG1 play a significant role in the regulation of neuronal cholesterol efflux to apoE discs and in suppression of APP processing to generate A? peptides. 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
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Rees, Martin D.; McNiven, Tane N.; Davies, Michael J.EPO (eosinophil peroxidase) and MPO (myeloperoxidase) are highly basic haem enzymes that can catalyse the production of HOBr (hypobromous acid). They are released extracellularly by activated leucocytes and their binding to the polyanionic glycosaminoglycan components of extracellular matrix (proteoglycans and hyaluronan) may localize the production of HOBr to these materials. It is shown in the present paper that the reaction of HOBr with glycosaminoglycans (heparan sulfate, heparin, chondroitin sulfate and hyaluronan) generates polymer-derived N-bromo derivatives (bromamines, dibromamines, N-bromosulfonamides and bromamides). Decomposition of these species, which can occur spontaneously and/or via one-electron reduction by low-valent transition metal ions (Cu+ and Fe2+), results in polymer fragmentation and modification. One-electron reduction of the N-bromo derivatives generates radicals that have been detected by EPR spin trapping. The species detected are consistent with metal ion-dependent polymer fragmentation and modification being initiated by the formation of nitrogen-centred (aminyl, N-bromo-aminyl, sulfonamidyl and amidyl) radicals. Previous studies have shown that the reaction of HOBr with proteins generates N-bromo derivatives and results in fragmentation of the polypeptide backbone. The reaction of HOBr with extracellular matrix synthesized by smooth muscle cells in vitro induces the release of carbohydrate and protein components in a time-dependent manner, which is consistent with fragmentation of these materials via the formation of N-bromo derivatives. The degradation of extracellular matrix glycosaminoglycans and proteins by HOBr may contribute to tissue damage associated with inflammatory diseases such as asthma. 2007 Biochemical Society.
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Nobourt, Estelle; Davies, Michael J.; Brown, Bronwyn E.; Curtiss, Linda K.; Bonnet, David J.; Charlton, Francesca; Januszewski, Andrzej S.; Jenkins, Alicia J.; Barter, Philip J.; Rye, Kerry AnneAims/hypothesis: Hyperglycaemia, one of the main features of diabetes, results in non-enzymatic glycation of plasma proteins, including apolipoprotein A-I (apoA-I), the most abundant apolipoprotein in HDL. The aim of this study was to determine how glycation affects the structure of apoA-I and its ability to activate lecithin:cholesterol acyltransferase (LCAT), a key enzyme in reverse cholesterol transport. Materials and methods: Discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and apoA-I ([A-I]rHDL) were prepared by the cholate dialysis method and glycated by incubation with methylglyoxal. Glycation of apoA-I was quantified as the reduction in detectable arginine, lysine and tryptophan residues. Methylglyoxal-AGE adduct formation in apoA-I was assessed by immunoblotting. (A-I)rHDL size and surface charge were determined by non-denaturing gradient gel electrophoresis and agarose gel electrophoresis, respectively. The kinetics of the LCAT reaction was investigated by incubating varying concentrations of discoidal (A-I)rHDL with a constant amount of purified enzyme. The conformation of apoA-I was assessed by surface plasmon resonance. Results: Methylglyoxal-mediated modifications of the arginine, lysine and tryptophan residues in lipid-free and lipid-associated apoA-I were time- and concentration-dependent. These modifications altered the conformation of apoA-I in regions critical for LCAT activation and lipid binding. They also decreased (A-I)rHDL size and surface charge. The rate of LCAT-mediated cholesterol esterification in (A-I)rHDL varied according to the level of apoA-I glycation and progressively decreased as the extent of apoA-I glycation increased. Conclusions/interpretation: It is concluded that glycation of apoA-I may adversely affect reverse cholesterol transport in subjects with diabetes. 2007 Springer-Verlag.
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Brown, Bronwyn E.; Rashid, Imran; Van Reyk, David M.; Davies, Michael J.Nonenzymatic covalent binding (glycation) of reactive aldehydes (from glucose or metabolic processes) to low-density lipoproteins has been previously shown to result in lipid accumulation in a murine macrophage cell line. The formation of such lipid-laden cells is a hallmark of atherosclerosis. In this study, we characterize lipid accumulation in primary human monocyte-derived macrophages, which are cells of immediate relevance to human atherosclerosis, on exposure to low-density lipoprotein glycated using methylglyoxal or glycolaldehyde. The time course of cellular uptake of low-density lipoprotein-derived lipids and protein has been characterized, together with the subsequent turnover of the modified apolipoprotein B-100 (apoB) protein. Cholesterol and cholesteryl ester accumulation occurs within 24 h of exposure to glycated low-density lipoprotein, and increases in a time-dependent manner. Higher cellular cholesteryl ester levels were detected with glycolaldehyde- modified low-density lipoprotein than with methylglyoxal-modified low-density lipoprotein. Uptake was significantly decreased by fucoidin (an inhibitor of scavenger receptor SR-A) and a mAb to CD36. Human monocyte-derived macrophages endocytosed and degraded significantly more 125I-labeled apoB from glycolaldehyde-modified than from methylglyoxal-modified, or control, low-density lipoprotein. Differences in the endocytic and degradation rates resulted in net intracellular accumulation of modified apoB from glycolaldehyde-modified low-density lipoprotein. Accumulation of lipid therefore parallels increased endocytosis and, to a lesser extent, degradation of apoB in human macrophages exposed to glycolaldehyde-modified low-density lipoprotein. This accumulation of cholesteryl esters and modified protein from glycated low-density lipoprotein may contribute to cellular dysfunction and the increased atherosclerosis observed in people with diabetes, and other pathologies linked to exposure to reactive carbonyls. 2007 The Authors.
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Rashid, Imran; Van Reyk, David M.; Davies, Michael J.Glycation of low-density lipoprotein (LDL) by reactive aldehydes, such as glycolaldehyde, can result in the cellular accumulation of cholesterol in macrophages. In this study, it is shown that carnosine, or its constituent amino acids ?-alanine and l-histidine, can inhibit the modification of LDL by glycolaldehyde when present at equimolar concentrations to the modifying agent. This protective effect was accompanied by inhibition of cholesterol and cholesteryl ester accumulation in human monocyte-derived macrophages incubated with the glycated LDL. Thus, carnosine and its constituent amino acids may have therapeutic potential in preventing diabetes-induced atherosclerosis. 2007 Federation of European Biochemical Societies.
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Orr, Yishay; Wilson, David P.; Taylor, Jude Matthew; Bannon, Paul Gerard; Geczy, Carolyn L.; Davenport, Miles P.; Kritharides, LeonardAcute inflammatory stimuli rapidly mobilize neutrophils from the bone marrow by shortening postmitotic maturation time and releasing younger neutrophils; however, the kinetics of this change in maturation time remains unknown. We propose a kinetic model that examines the rate of change in neutrophil average age at exit from the bone marrow during active mobilization to quantify this response and use this model to examine the temporal profile of late neutrophil phenotypic maturation. Total and CD10-/CD16 low circulating neutrophils were quantified in cardiac surgery patients during extracorporeal circulation (ECC). Net growth in the circulating neutrophil pool occurred during the procedural (0.04 0.02 109l-1min-1), warming (0.14 0.02 109l-1min -1), and weaning (0.12 0.06 109 l-1 min-1) phases of ECC. When applied to our differential equation mathematical model, these results predict that neutrophil average age at exit from the bone marrow decreased continually during ECC, resulting in average neutrophil release 8.44 2.20 h earlier during the weaning phase than at the beginning of ECC sampling. Modeling of concurrent changes in CD10-/CD16low neutrophil numbers indicates that CD10 expression is directly related to neutrophil mean age and predicts that the proportion of mobilizable postmitotic neutrophils that are CD10+ increases from 64 to 81% during these sampled 8.4 h of maturation. Copyright 2007 the American Physiological Society.
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Sumi, Makoto; Sata, Masataka; Miura, Shinichiro; Rye, Kerry Anne; Toya, Naoki; Kanaoka, Yuji; Yanaga, Katsuhiko; Ohki, Takao; Saku, Keijiro; Nagai, RyozoBACKGROUND - Plasma high-density lipoprotein (HDL) levels have an inverse correlation with incidence of ischemic heart disease as well as other atherosclerosis-related ischemic conditions. However, the molecular mechanism by which HDL prevents ischemic disease is not fully understood. Here, we investigated the effect of HDL on differentiation of endothelial progenitor cells and angiogenesis in murine ischemic hindlimb model. METHODS AND RESULTS - Intravenous injection of reconstituted HDL (rHDL) significantly augmented blood flow recovery and increased capillary density in the ischemic leg. rHDL increased the number of bone marrow-derived cells incorporated into the newly formed capillaries in ischemic muscle. rHDL induced phosphorylation of Akt in human peripheral mononuclear cells. rHDL (50 to 100 ?g apolipoprotein A-I/mL) promoted differentiation of peripheral mononuclear cells to endothelial progenitor cells in a dose-dependent manner. The effect of rHDL on endothelial progenitor cells differentiation was abrogated by coadministration of LY294002, an inhibitor of phosphatidylinositol 3-kinase. rHDL failed to promote angiogenesis in endothelial NO-deficient mice. CONCLUSIONS - rHDL directly stimulates endothelial progenitor cell differentiation via phosphatidylinositol 3-kinase/Akt pathway and enhances ischemia-induced angiogenesis. rHDL may be useful in the treatment of patients with ischemic cardiovascular diseases. 2007 American Heart Association, Inc.
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Kennett, Eleanor C.; Davies, Michael J.The oxidant peroxynitrite/peroxynitrous acid (ONOO-/ONOOH) is generated at sites of inflammation via reaction of O<inf>2</inf>{radical dot}- with {radical dot}NO. Previous studies have shown that these species can oxidize cellular targets, but few data are available on damage to extracellular matrix and its components, despite evidence for matrix modification in a number of pathologies. In the current study we show that reaction of ONOO-/ONOOH with glycosaminoglycans results in extensive polymer fragmentation. Bolus authentic ONOO-/ONOOH modifies hyaluronan, heparin, and chondroitin, dermatan, and heparan sulfates, in a concentration-dependent, but O<inf>2</inf>-independent, manner. The ONOO-/ONOOH generator 3-(4-morpholinyl)sydnoneimine produces similar time- and concentration-dependent damage. These reactions generate specific polymer fragments via cleavage at disaccharide intervals. Studies at different pH values, and in the presence of bicarbonate, are consistent with ONOOH, rather than the carbonate adduct, CO<inf>3</inf>{radical dot}- or ONOO-, being the source of damage. EPR spin trapping experiments have provided evidence for the formation of carbon-centered radicals on glycosaminoglycans and related monosaccharides; the similarity of these spectra to those obtained with authentic HO{radical dot} is consistent with fragmentation being induced by this oxidant. These data suggest that extracellular matrix fragmentation at sites of inflammation may be due, in part, to the formation and reactions of ONOOH. 2007 Elsevier Inc. All rights reserved.
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Kastelein, Johannes Jacob Pieter; van Leuven, Sander I.; Burgess, Leslie; Evans, Gregory W.; Kuivenhoven, Jan Albert; Barter, Philip J.; Revkin, James H.; Grobbee, Diederick E Egbertus; Riley, Ward A.; Shear, Charles L.; Duggan, William T.; Bots, Michiel L.Background: Torcetrapib, an inhibitor of cholesteryl ester transfer protein, may reduce atherosclerotic vascular disease by increasing levels of high-density lipoprotein (HDL) cholesterol. Methods: A total of 850 patients with heterozygous familial hypercholesterolemia underwent B-mode ultrasonography at baseline and at follow-up to measure changes in carotid intima-media thickness. The patients completed an atorvastatin run-in period and were subsequently randomly assigned to receive either atorvastatin monotherapy or atorvastatin combined with 60 mg of torcetrapib for 2 years. Results: After 24 months, in the atorvastatin-only group, the mean (SD) HDL cholesterol level was 52.413.5 mg per deciliter and the mean low-density lipoprotein (LDL) cholesterol level was 143.242.2 mg per deciliter, as compared with 81.522.6 mg per deciliter and 115.148.5 mg per deciliter, respectively, in the torcetrapib-atorvastatin group. During the study, average systolic blood pressure increased by 2.8 mm Hg in the torcetrapib-atorvastatin group, as compared with the atorvastatin-only group. The increase in maximum carotid intima-media thickness, the primary measure of efficacy, was 0.00530.0028 mm per year in the atorvastatin-only group and 0.00470.0028 mm per year in the torcetrapib-atorvastatin group (P=0.87). The secondary efficacy measure, annualized change in mean carotid intima-media thickness for the common carotid artery, indicated a decrease of 0.0014 mm per year in the atorvastatin-only group, as compared with an increase of 0.0038 mm per year in the torcetrapib-atorvastatin group (P=0.005). Conclusions: In patients with familial hypercholesterolemia, the use of torcetrapib with atorvastatin, as compared with atorvastatin alone, did not result in further reduction of progression of atherosclerosis, as assessed by a combined measure of carotid arterial-wall thickness, and was associated with progression of disease in the common carotid segment. These effects occurred despite a large increase in HDL cholesterol levels and a substantial decrease in levels of LDL cholesterol and triglycerides. Copyright 2007 Massachusetts Medical Society.
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Wu, Ben Jing; Di Girolamo, Nick; Beck, Konstanze; Hanratty, Colm Gerard; Choy, Katherine J.; Hou, Jingyun; Ward, Michael R.; Stocker, RolandProbucol [4,4?-[(1-methylethylidene)bis(thio)]bis-[2,6-bis(1,1- dimethylethyl)phenol]] was withdrawn from the United States market because it failed to inhibit atherosclerosis in human femoral arteries, yet the drug was shown subsequently to inhibit atherosclerosis in human carotid arteries, and probucol monosuccinate ester is presently being tested in a phase III clinical trial as an antiatherosclerotic compound based on its anti-inflammatory properties. Inflammatory macrophages are implicated in arterial remodeling associated with atherosclerosis, and probucol inhibits experimental atherosclerosis in part by decreasing macrophages in lesions. However, the impact of probucol on remodeling is unknown, although such knowledge could help explain why the drug's benefit on human atherosclerosis is controversial. We therefore examined the effect of probucol on remodeling of the common carotid artery in apolipoprotein E-deficient mice. We observed that during de novo atherosclerosis, plaque growth was fully compensated by expansive remodeling, such that lumen area was unaffected. Early lesions were composed almost entirely of macrophages, and their contribution to lesion area progressively decreased thereafter. Probucol significantly decreased plaque area, expression of vascular cell adhesion molecule-1, and proliferation of intimal cells, resulting in delayed macrophage accumulation in the vessel. Probucol also decreased the production and activity of matrix metalloproteinases-2 and -9, independent of the plasmin protease system, and this was associated with an inhibition of expansive remodeling, resulting in lumen loss. These studies show that probucol attenuates compensatory remodeling associated with de novo atherosclerosis, probably via its anti-inflammatory properties. Our findings suggest that lumen volume is not a suitable surrogate to assess the antiatherosclerotic activity of probucol and related drugs. Copyright 2007 by The American Society for Pharmacology and Experimental Therapeutics.
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Rashid, Imran; Brown, Bronwyn E.; Van Reyk, David M.; Davies, Michael J.Diabetes is known to induce a range of micro-and macrovascular complications, with the latter resulting in premature and accelerated atherosclerosis. Thus people with diabetes have a 2-4-fold increased risk of developing cardiovascular diseases which is responsible for ca. 50% of deaths amongst people with diabetes. The mechanisms behind this elevated risk are still not fully understood, though there is now increasing evidence for a role of glycation and glycoxidation reactions induced by hyperglycemia. This article reviews current knowledge of the role that these reactions play in diabetesinduced atherosclerosis with particular emphasis on the molecular reactions that result in the modification of lipoproteins, and the consequences of these reactions on cellular metabolism. 2006 Springer Science+Business Media, LLC. All rights reserved.
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Zeng, Jingmin; Davies, Michael J.Protein glycation has been implicated in the aging process as well as the complications of diabetes (retinopathy, neuropathy, nephropathy, and atherosclerosis). The nitrogen substituents of Lys, Arg, and His residues and the N-terminus of proteins are known to be readily glycated. As the thiol group of Cys is a powerful nucleophile, we hypothesized that Cys residues should also be targets of glycation and that low molecular mass thiols may act as protective agents. In this study the role of thiol glycation, induced by dicarbonyls, in protein cross-link formation and damage prevention is examined. It is shown that incubation of creatine kinase with glyoxal results in protein cross-link formation, with this occurring concurrently with loss of thiol groups, enzyme inactivation, and formation of S-carboxymethylcysteine, a product of glyoxal adduction to Cys residues. Cross-links have also been detected between W-acetylcysteine and the Lys-rich protein histone H1, demonstrating the formation of thiol-glyoxalamine cross-links. Mass spectrometry has been used to characterize some of these cross-links as 2-(alkylthio)acetamides. A range of low molecular mass thiols have been shown to inhibit dicarbonyl adduction to, and cross-linking of, the thiol-free protein lysozyme, consistent with these thiols being alternative (sacrificial) targets of glycation. Some of these thiols are more efficient modulators of glycation than established glycation inhibitors such as aminoguanidine. These data demonstrate that thiols are facile targets of glycation and that low molecular mass thiols are potent glycation inhibitors. These data may aid the design of therapeutic agents for the treatment of the complications of diabetes. 2006 American Chemical Society.
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Ooi, Esther M.; Watts, Gerald F.; Ji, Juying; Rye, Kerry Anne; Johnson, Anthony G.; Chan, Dick C.F.; Barrett, Hugh Hugh R.Objective: Phospholipid transfer protein (PLTP) is an important regulator in the transport of surface components of triglyceride-rich lipoprotein (TRL) to high density lipoprotein (HDL) during lipolysis and may therefore play an important role in regulating HDL transport. In this study we investigated the relationship of plasma PLTP activity with HDL metabolism in men. Design and methods: The kinetics of HDL LpA-I and LpA-I:A-II were measured using intravenous administration of [d<inf>3</inf>]-leucine, gas chromatography-mass spectrometry (GCMS) and a new multicompartmental model for HDL subpopulation kinetics (SAAM II) in 31 men with wide-ranging body mass index (BMI 18-46 kg/m2). Plasma PLTP activity was determined as the transfer of radiolabelled phosphatidylcholine from small unilamellar phosphatidylcholine vesicles to ultracentrifugally isolated HDL. Results: PLTP activity was inversely associated with LpA-I concentration and production rate (PR) after adjusting for insulin resistance (P < 0.05). No significant associations were observed between plasma PLTP activity and LpA-I fractional catabolic rate (FCR). In multivariate analysis, including homeostasis model assessment score (HOMA), triglyceride, cholesteryl ester transfer protein (CETP) activity and PLTP activity, PLTP activity was the only significant determinant of LpA-I concentration and PR (P = 0.020 and P = 0.016, respectively). Conclusions: Plasma PLTP activity may be a significant, independent determinant of LpA-I kinetics in men, and may contribute to the maintenance of the plasma concentration of these lipoprotein particles in setting of hypercatabolism of HDL. 2006 The Authors.
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Chapman, Caroline L.; McQuillan, Brendan M.; Beilby, John P.; Thompson, Peter Lindsay; Hung, Joseph C.Interleukin (IL)-18 is a novel proinflammatory cytokine that plays a central role in innate and acquired immunity, making it a likely inflammatory candidate in atherosclerosis. We investigated whether circulating IL-18 levels were associated with subclinical atherosclerosis in a community population. Carotid intimal medial thickness (IMT) and carotid plaques were assessed in a cross-sectional study of 1111 randomly selected community subjects, aged 27-77 years. Baseline levels of IL-18, IL-6, high sensitive CRP (hsCRP), fibrinogen and white cell counts were measured along with conventional cardiovascular risk factors. Men had higher mean IL-18 levels than women (P < 0.0001). Spearman rank correlations (r<inf>s</inf>) showed that IL-18 was weakly correlated with all inflammatory markers in the whole population (r<inf>s</inf> between 0.11 and 0.23, all P < 0.001). IL-18 was also correlated with conventional risk factors including waist-hip ratio, BMI, blood pressure, triglycerides, HDL (inversely) and pack-years smoking (r<inf>s</inf> between 0.18 and 0.39, all P < 0.001) but not with LDL-cholesterol. Independent predictors of IL-18 concentrations were waist-hip ratio, HDL, IL-6, hsCRP and hypertension. There was a positive univariate association of IL-18 levels with carotid IMT (P < 0.001) and plaque prevalence (P < 0.001) but no residual association after adjustment for conventional risk factors (both P > 0.05). In a cross-sectional community population, IL-18 levels were related to traditional risk factors and inflammatory markers but were not independently associated with subclinical carotid atherosclerosis. 2006 Elsevier Ireland Ltd. All rights reserved.
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Cohn, Jeffrey S.[No abstract available]
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Moran, Damian; Jacob, Rebecca; Wood, Geoffrey P.F.; Coote, Michelle L.; Davies, Michael J.; O'Hair, Richard A.J.; Easton, Christopher J.; Radom, LeoIntramolecular H-atom transfer in model peptide-type radicals was investigated with high-level quantum-chemistry calculations. Examination of 1,2-, 1,3-, 1,5-, and 1,6[C ? N]-H shifts, 1,4- and 1,7[C ? C]-H shifts, and 1,4[N ? N]-H shifts (Scheme 1), was carried out with a number of theoretical methods. In the first place, the performance of UB3-LYP (with the 6-31G(d), 6-31G(2df,p), and 6-311+G(d,p) basis sets) and UMP2 (with the 6-31G(rf) basis set) was assessed for the determination of radical geometries. We found that there is only a small basis-set dependence for the UB3-LYP structures, and geometries optimized with UB3-LYP/6-31G(d) are generally sufficient for use in conjunction with high-level composite methods in the determination of improved H-transfer thermochemistry. Methods assessed in this regard include the high-level composite methods, G3(MP2)-RAD, CBS-QB3, and G3//B3-LYP, as well as the density-functional methods B3-LYP, MPWB1K, and BMK in association with the 6-31+G(d,p) and 6-311++G(3df,3pd) basis sets. The high-level methods give results that are close to one another, while the recently developed functionals MPWB1K and BMK provide cost-effective alternatives. For the systems considered, the transformation of an N-centered radical to a C-centered radical is always exothermic (by 25 kJ mol -1 or more), and this can lead to quite modest barrier heights of less than 60 kJ mol -1 (specifically for 1,5[C ? N]-H and 1,6[C ? N]-H shifts). H-Migration barriers appear to decrease as the ring size in the transition structure (TS) increases, with a lowering of the barrier being found, for example when moving from a rearrangement proceeding via a four-membered-ring TS (e.g., the 1,3[C ? N]-H shift, CH <inf>3</inf>-C(O)-NH . ? .CH <inf>2</inf>-C(O)-NH <inf>2</inf>) to a rearrangement proceeding via a six-membered-ring TS (e.g., the 1,5[C ? N]-H shift, .NH-CH <inf>2</inf>-C(O)-NH-CH <inf>3</inf> ? NH <inf>2</inf>-CH <inf>2</inf>-C(O)-NH-CH <inf>2</inf> .). 2006 Verlag Helvetica Chimica Acta AG.
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Dunn, Louise L.; Sekyer, E. O.; Suryo Rahmanto, Yohan; Richardson, Des RaymondMelanotransferrin (MTf) or melanoma tumor antigen p97 is an iron (Fe) binding transferrin homolog expressed highly on melanomas and at lower levels on normal tissues. It has been suggested that MTf is involved in a variety of processes such as Fe metabolism and cellular differentiation. Considering the crucial role of Fe in many metabolic pathways, for example, DNA synthesis, it is important to understand the function of MTf. To define the roles of MTf, two models were developed: (i) an MTf knockout (MTf-/-) mouse and (ii) downregulation of MTf expression in melanoma cells by post-transcriptional gene silencing (PTGS). Examination of the MTf-/- mice demonstrated no differences compared with wild-type littermates. However, microarray analysis showed differential expression of molecules involved in proliferation such as Mef2a, Tcf4, Gls and Apod in MTf-/- mice compared with MTf+/+ littermates. Considering the role of MTf in melanoma cells, PTGS was used to downregulate MTf mRNA and protein levels by >90 and >80%, respectively. This resulted in inhibition of proliferation and migration. As found in MTf-/- mice, in melanoma cells with suppressed MTf expression, hMEF2A and hTCF4 were upregulated compared with parental cells. Furthermore, when melanoma cells with decreased MTf expression were injected into nude mice, tumor growth was markedly reduced, suggesting a role for MTf in proliferation and tumorigenesis. 2006 Oxford University Press.
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Waters, David D.; LaRosa, John C.; Barter, Philip J.; Fruchart, Jean Charles; Gotto, Antonio M.; Carter, Roddy; Breazna, Andrei; Kastelein, Johannes Jacob Pieter; Grundy, Scott M.Objective: We sought to assess the effects on cerebrovascular events of treating patients with stable coronary disease with low-density lipoprotein cholesterol (LDL-C) levels substantially below 100 mg/dl. Background: Lowering LDL-C with statins has been shown to reduce the risk of stroke in patients with stable coronary disease. In observational studies, naturally low cholesterol levels have been associated with an increased risk of hemorrhagic stroke. The cerebrovascular benefits of treating patients with stable coronary disease to LDL-C levels substantially below 100 mg/dl have not been previously investigated. Methods: We describe an analysis of cerebrovascular events in the Treating to New Targets study, a trial where 10,001 patients with documented coronary disease were randomized to treatment with atorvastatin at 10 mg/day or 80 mg/day and followed for a median of 4.9 years. Results: Mean LDL-C levels were 101 mg/dl on 10 mg atorvastatin and 77 mg/dl on 80 mg. In addition to the reduction in major cardiovascular events (hazard ratio 0.78, 95% confidence interval [CI] 0.69 to 0.89; p = 0.0002), the primary end point of the trial, patients in the 80-mg arm experienced a reduction in cerebrovascular events (hazard ratio 0.77, 95% CI 0.64 to 0.93; p = 0.007) and stroke (hazard ratio 0.75, 95% CI 0.59 to 0.96; p = 0.02). Each 1-mg/dl reduction in LDL-C with treatment was associated with a 0.6% relative risk reduction in cerebrovascular events (p = 0.002) and a 0.5% relative risk reduction in stroke (p = 0.041). The incidence of hemorrhagic stroke was similar in the 80-mg and 10-mg groups, 16 and 18 respectively, and the hemorrhagic strokes were distributed evenly across quintiles of achieved LDL-C during treatment. Conclusions: Among patients with established coronary disease, treating to an LDL-cholesterol substantially below 100 mg/dl with 80 mg/day atorvastatin reduces both stroke and cerebrovascular events by an additional 20% to 25% compared with the 10 mg/day dose. An increase in hemorrhagic stroke was not seen at low LDL-C levels. (Treating to New Targets; http://www.clinicaltrials.gov; NCT00327691). 2006 American College of Cardiology Foundation.
