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Showing 1381–1400 of 2058 publications.
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Homer, Vivienne M.; Marais, Adrian David; Charlton, Francesca; Laurie, Andrew D.; Hurndell, Nicola; Scott, R. S.; Mangili, Fabien; Sullivan, David R.; Barter, Philip J.; Rye, Kerry Anne; George, Peter Myles; Lambert, GillesWe analysed the Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) exons and intronic junctions of 71 patients with familial hypercholesterolemia (FH) in whom LDL receptor (LDLR) or apolipoprotein B100 mutations were excluded. The previously reported S127R and R237W mutations were found in South African families, whereas new missense mutations D129G and A168E were found in families from New Zealand. Only, the S127R and D129G mutations modify a highly conserved residue and segregate with the FH phenotype. We overexpressed those mutants in hepatoma cells and found that both S127R and D129G have reduced autocatalytic activity compared with wild-type PCSK9, whereas the A168E mutant is processed normally. The S127R and D129G mutants were not secreted from cells, unlike the A168E mutant and wild-type PCSK9. By immunoblot, we showed that the expression of the LDLR was reduced by 40% in cells overexpressing wild-type or A168E PCSK9 and further reduced by 30% when the S127R or D129G mutants were used. Paralleling the LDLR levels, LDL cellular binding decreased by 25% upon wild-type PCSK9 or A168E overexpression, and by 45% with both S127R and D129G mutants. Our study therefore indicates that PCSK9 mediated inhibition of the LDLR does not require PCSK9 autocatalytic cleavage or secretion, suggesting that PCSK9 may also function intracellularly. 2007 Elsevier Ireland Ltd. All rights reserved.
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Skilton, Michael R.; Sieveking, Daniel P.; Harmer, Jason A.; Franklin, Janet L.; Loughnan, Georgina T.; Nakhla, Shirley; Sullivan, David R.; Caterson, Ian Douglas; Celermajer, David S.Aims: The mechanisms by which obesity confers increased cardiovascular risk and the effects of moderate weight loss on cardiovascular health are incompletely understood. We sought to characterize the preclinical changes in cardiac and vascular health that accompany obesity and the influence of lifestyle modification on these parameters. Methods: Preclinical markers of vasculopathy in resistance vessels and conduit arteries and left ventricular structure and function were assessed in 39 obese subjects (BMI>30 kg/m2) and 11 healthy weight controls. The influence of serum on cellular adhesion molecule (CAM) expression on human endothelial cells was studied ex vivo in a subgroup of 13 obese and nine healthy weight subjects. These analyses were repeated in all 17 of the obese subjects who complied with 4-9 months of lifestyle modification treatment (six with weight loss >5% and 11 with weight loss <5%). Results: Compared with healthy weight controls, obese subjects had decreased peak hyperaemic forearm blood flow (p = 0.015), increased carotid intima-media thickness (p = 0.009), increased left ventricular wall thickness and volume and evidence of systolic and diastolic dysfunction as assessed using tissue Doppler imaging (S?, p = 0.09; E?/A?, p = 0.02), and serum from obese subjects increased the intercellular CAM-1 expression on human endothelial cells (p = 0.009). However, arterial endothelial function assessed by flow-mediated dilatation was not altered (p=0.99). Lifestyle modification treatment resulted in potentially beneficial changes in fibrinogen (p = 0.003), HDL cholesterol (p = 0.05) and soluble vascular CAM-1 (p = 0.06). In subjects with weight loss greater than 5% of body weight, there was also a decrease in low-level inflammation (high-sensitivity C-reactive protein, p = 0.05), lipid peroxidation (thiobarbituric acid-reactive substances, p = 0.05) and triglycerides (p = 0.07). Conclusions: Obesity is associated with widespread alterations in cardiac and vascular structure and function. Moderate short-term weight loss by lifestyle modification results in some beneficial changes in serum profile; however, these are not accompanied by significant alterations to either cardiac or vascular structure and function. 2007 The Authors Journal Compilation 2007 Blackwell Publishing Ltd.
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Glaros, Elias N.; Kim, Woojin Scott; Rye, Kerry Anne; Shayman, James Alan; Garner, BrettGlycosphingolipids (GSLs) have been implicated as potential atherogenic lipids. Studies in apolipoprotein E-null (apoE-/-) mice indicate that exacerbated tissue GSL accumulation resulting from a-galactosidase deficiency promotes atherosclerosis, whereas the serine palmitoyl transferase inhibitor myriocin (which reduces plasma and tissue levels of several sphingolipids, including sphingomyelin, ceramide, sphingosine-1-phosphate, and GSLs) inhibits atherosclerosis. It is not clear whether GSL synthesis inhibition per se has an impact on atherosclerosis. To address this issue, apoE-/- mice maintained on a high-fat diet were treated with a potent glucosylceramide synthesis inhibitor, D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (EtDO-P4), 10 mg/kg/day for 94 days, and lesion development was compared in mice that were treated with vehicle only. EtDO-P4 reduced plasma GSL concentration by approximately 50% but did not affect cholesterol or triglyceride levels. Assessment of atherosclerotic lesions at four different sites indicated that EtDO-P4 had no significant impact on lesion area. Thus, despite the previously observed positive correlations between plasma and aortic GSL concentrations and the development of atherosclerosis, and the in vitro evidence implying that GSLs may be pro-atherogenic, our current data indicate that inhibition of GSL synthesis does not inhibit atherosclerosis in vivo. Copyright 2008 by the American Society for Biochemistry and Molecular Biology, Inc.
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Duez, He; Lamarche, Beno ?t; Uffelman, Kristine D.; Valo, Ren Szeto, Linda W.; Lemieux, Simone; Cohn, Jeffrey S.; Lewis, Gary FranklinContext: Despite its potent, well-documented insulin-sensitizing effects, rosiglitazone (RSG) does not effectively ameliorate the hypertriglyceridemia of insulin-resistant or diabetic individuals and has even been shown to slightly but significantly increase triglyceride-rich lipoproteins (TRL) in some studies. The mechanism of this effect is currently not known. Objective: We investigated the effect of RSG treatment on TRL metabolism. Design: This was a 12-wk, single-sequence, cross-over study of rosiglitazone vs. placebo for 6 wk. Participants: Participants included 17 nondiabetic men with a broad range of insulin sensitivity. Intervention: Intervention included rosiglitazone 8 mg/d vs. placebo for 6 wk. Main Outcome Measure: TRL metabolism (concentration, production and catabolic rates) was assessed in a constant fed state with a 12-h primed constant infusion of [D3]L-leucine and multicompartmental modeling. Results: RSG treatment resulted in significant insulin sensitization with no change in body weight. Fasting plasma triglyceride (TG) concentration, however, was higher with RSG vs. placebo (P = 0.0006), as were fasting and fed TRL-TG, TRL-apoB-48, and TRL-apoB-100 (fed TRL-apoB-48: 0.93 0.08 vs. 0.76 0.07 mg/dl, P = 0.017, and fed TRL-apoB-100: 15.57 0.90 vs. 13.71 1.27 mg/dl, P = 0.029). This small but significant increase in plasma TRL concentration was explained by a tendency for RSG to increase TRL production and reduce particle clearance, as indicated by the significantly increased production to clearance ratios for both apoB-48-containing (0.43 0.03 vs. 0.34 0.03, P = 0.048) and apoB-100-containing (7.0 0.4 vs. 6.2 0.6, P = 0.029) TRL. Conclusion: These data indicate dissociation between the insulin-sensitizing effects of RSG and absence of anticipated reductions in production rates of apoB-100- and apoB-48-containing-TRL particles, which may explain the absence of TG lowering seen in humans treated with this agent. Copyright 2008 by The Endocrine Society.
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Sandhu, Manjinder Singh; Waterworth, Dawn M.; Debenham, Sally L.; Wheeler, Eleanor; Papadakis, Konstantinos; Zhao, Jinghua; Song, Kjioung S.; Yuan, Xin; Johnson, Toby; Ashford, Sofie E.; Inouye, Michael T.; Luben, Robert N.; Sims, Matthew A.; Hadley, David J.; McArdle, Wendy L.; Barter, Philip J.; Kesaniemi, YrjAntero; Mahley, Robert W.; McPherson, Ruth M.; Grundy, Scott M.; Bingham, Sheila Anne; Khaw, Kay Tee T.; Loos, Ruth J.f.; Waeber, Gard; Barroso, In E.; Strachan, David Peter; Deloukas, Panos; Vollenweider, Peter K.; Wareham, Nicholas J.; Mooser, Vincent E.Background: LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations. Methods: We used genome-wide association data from up to 11 685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290 140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations. Findings: In our initial scan, we found two SNPs (rs599839 [p=170-15] and rs4970834 [p=300-11]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=430-9]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=120-33) and rs646776 (p=480-20) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L. Interpretation: We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease. 2008 Elsevier Ltd. All rights reserved.
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Settasatian, Nongnuch; Barter, Philip J.; Rye, Kerry AnnePhospholipid transfer protein (PLTP) transfers phospholipids between HDL and other lipoproteins in plasma. It also remodels spherical, apolipoprotein A-I (apoA-I)-containing HDL into large and small particles in a process involving the dissociation of lipid-free/lipid-poor apoA-I. ApoE is another apolipoprotein that is mostly associated with large, spherical HDL that do not contain apoA-I. Three isoforms of apoE have been identified in human plasma: apoE2, apoE3, and apoE4. This study investigates the remodeling of spherical apoE-containing HDL by PLTP and the ability of PLTP to transfer phospholipids between apoE-containing HDL and phospholipid vesicles. Spherical reconstituted high density lipoproteins (rHDL) containing apoA-I [(A-I)rHDL], apoE2 [(E2)rHDL], apoE3 [(E3)rHDL], or apoE4 [(E4)rHDL] as the sole apolipoprotein were prepared by incubating discoidal rHDL with low density lipoproteins and lecithin:cholesterol acyltransferase. PLTP remodeled the spherical, apoE-containing rHDL into large and small particles without the dissociation of apoE. The PLTP-mediated remodeling of apoE-containing rHDL was more extensive than that of (A-I)rHDL. PLTP transferred phospholipids from small unilamellar vesicles to apoE-containing rHDL in an isoform-dependent manner, but at a rate slower than that for spherical (A-I)rHDL. It is concluded that apoE enhances the capacity of PLTP to remodel HDL but reduces the ability of HDL to participate in PLTP-mediated phospholipid transfers. Copyright 2008 by the American Society for Biochemistry and Molecular Biology, Inc.
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Puranik, Rajesh; Bao, Shishan San; Nobourt, Estelle; Nicholls, Stephen J.; Dusting, Gregory James; Barter, Philip J.; Celermajer, David S.; Rye, Kerry AnneThis study investigates the ability of a single, low dose of apolipoprotein (apo) A-I, the main lipoprotein of high density lipoproteins (HDL), to inhibit acute vascular inflammation in normocholesterolemic New Zealand White rabbits. Acute vascular inflammation was induced in the animals by placing a non-occlusive, silastic collar around the left common carotid artery. The animals (n = 5/group) received a single, low dose infusion of saline or lipid-free apoA-I at the time of, or 3 or 9 h after collar insertion. The animals were sacrificed 24 h post-collar insertion. Inflammatory markers in the artery wall were quantitated immunohistochemically. The saline-treated animals exhibited substantial pan-arterial inflammation, which was inhibited by a single apoA-I infusion (2 or 8 mg/kg) at the time of collar insertion. A single 8 mg/kg infusion of lipid-free apoA-I administered 3 h post-collar insertion reduced neutrophil recruitment into the vessel wall, and MPO expression, as well as endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by >85% (p < 0.01 for all). A single 8 mg/kg infusion of lipid-free apoA-I administered 9 h after collar insertion decreased VCAM-1 expression, neutrophil infiltration and MPO expression by 88% (p < 0.001), 47% (p < 0.01), and 90% (p < 0.01), respectively. This indicates that a single low dose infusion of apoA-I administered after the onset of acute inflammation in carotid arteries decreases neutrophil infiltration and inhibits neutrophil and endothelial cell activation. These findings have potential implications for treating acute vascular inflammation in conditions such as acute coronary and stroke syndromes. 2007 Elsevier Ireland Ltd. All rights reserved.
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Barter, Philip J.; Rye, Kerry AnneThe outcomes of fibrate trials have varied: positive with gemfibrozil in the primary prevention Helsinki Heart Study and the secondary prevention VA-HIT trial; positive with reservations in the primary prevention WHO trial (clofibrate); and mixed with bezafibrate in the secondary prevention BIP study and with fenofibrate in the combined primary and secondary prevention FIELD study. Overall, the mixed results, combined with potential for adverse effects when given in combination with statins, have limited the use of these fibrates as cardioprotective agents. However, post hoc analyses of several of the fibrate studies have shown that people with features of the metabolic syndrome, particularly overweight people with high plasma triglyceride levels and low levels of HDL cholesterol, derive a disproportionately large reduction in cardiovascular events when treated with these agents. Thus, there is a strong case for the use of a fibrate to reduce the cardiovascular risk in overweight people with high triglyceride and low HDL-C. However, it should be noted that such people also have their cardiovascular risk reduced by statin therapy. It remains to be determined whether the combination of a fibrate plus statin reduces the risk beyond that achieved with a statin alone. 2008 American Heart Association, Inc.
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Barter, Philip J.[No abstract available]
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Kim, Woojin Scott; Elliott, David A.; Kockx, Maae; Kritharides, Leonard; Rye, Kerry Anne; Jans, David Andrew; Garner, BrettPrevious results indicate that apoE (apolipoprotein E) may be associated with the nucleus in specific cell types, particularly under stress conditions such as serum starvation. In addition, nuclear apoE localization in ovarian cancer was recently shown to be correlated with patient survival. In order to better understand the factors associated with apoE nuclear localization, we examined intracellular apoE trafficking using live-cell imaging of CHO (Chinese-hamster ovary) cells that constitutively expressed apoE-GFP (green fluorescent protein). In addition, we used biotinylated apoE (in a lipid-free state and as a lipidated discoidal complex) to track the uptake and potential nuclear targeting of exogenous apoE. Our results indicate that a small proportion of apoE-GFP is detected in the nucleus of living apoE-GFP-expressing CHO cells and that the level of apoE-GFP in the nucleus is increased with serum starvation. Exposure of control CHO cells to exogenous apoE-GFP did not result in nuclear apoE-GFP localization in the recipient cells. Similarly, biotinylated apoE did not reach the nucleus of control CHO cells or SK-N-SH neurons. In contrast, when biotinylated apoE was delivered to recipient cells as a lipidated apoE disc, apoE was detected in the nucleus, suggesting that the lipoprotein complex alters the intracellular degradation or trafficking of apoE. Biotinylated apoE discs containing each of the three common human apoE isoforms (E2, E3 and E4) were also tested for nuclear trafficking. All three apoE isoforms were equally detected in the nucleus. These studies provide new evidence that apoE may be targeted to the nucleus and shed light on factors that regulate this process. The Authors Journal compilation.
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Dremina, Elena S.; Sharov, Victor S.; Davies, Michael J.; Scheich, Christian S.The oxidative modification of proteins plays an important role in a wide range of pathological processes and aging. Proteins are modified by numerous biologic oxidants including hydrogen peroxide, peroxynitrite, singlet oxygen, and oxygen- and nitrogen-centered radicals. More recently, an additional class of physiologically important oxidants has been identified, peptide and protein peroxides. The latter react quite rapidly and selectively with protein cysteine residues. The sarco/endoplasmic reticulum Ca-ATPase (SERCA) is reversibly regulated through NO-dependent S-glutathiolation of specific cysteine residues. The irreversible oxidation of these cysteine residues could, therefore, impair NO-dependent muscle relaxation. Here, we show that specific protein-derived (amino acid) peroxides react selectively with a subset of the 22 reduced cysteine residues of SERCA1, including a peptide-containing Cys674 and Cys675, where Cys674 (in SERCA2) represents one of the targets for NO-dependent S-glutathiolation. Out of 11 tested amino acid, peptide, and protein peroxides, those derived from free tryptophan and free tyrosine showed the highest reactivity towards SERCA, while no oxidation under similar experimental conditions was detected through hydrogen peroxide. Among the peroxides from tryptophan, those of free tryptophan showed a significantly higher reactivity as compared to those from N- and C-terminally blocked tryptophan. Quantitative HPLC-MS/MS analysis demonstrated that the highest reactivity of the tryptophan-derived peroxides was observed for Cys774 and Cys938, cysteine residues, which are embedded within the transmembrane domains of SERCA1. This unusual reactivity of transmembrane domains cannot be solely rationalized by the hydrophobicity of the oxidant, as the peroxide from DL-tryptophan shows considerable higher reactivity as compared to the one derived from N-acetyl-tryptophan methyl ester. Our data demonstrate a potential role of peptide- and protein-derived peroxides as important mediators of oxidative stress in vivo, which may cause a selective oxidation of Cys residues leading to inactivation of membrane proteins. 2007 American Chemical Society.
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Balkau, Beverley J.; Deanfield, John Eric; Despr, Jean Pire; Bassand, Jean Pierre L.; Fox, Keith A.A.; Smith, Sidney C.; Barter, Philip J.; Tan, Cheeeng; van Gaal, Luc F.; Wtchen, Hans rich; Massien, Christine; Haffner, Steven M.BACKGROUND - Abdominal adiposity is a growing clinical and public health problem. It is not known whether it is similarly associated with cardiovascular disease (CVD) and diabetes mellitus in different regions around the world, and thus whether measurement of waist circumference (WC) in addition to body mass index (BMI) is useful in primary care practice. METHODS AND RESULTS - Randomly chosen primary care physicians in 63 countries recruited consecutive patients aged 18 to 80 years on 2 prespecified half days. WC and BMI were measured and the presence of CVD and diabetes mellitus recorded. Of the patients who consulted the primary care physicians, 97% agreed to participate in the present study. Overall, 24% of 69 409 men and 27% of 98 750 women were obese (BMI?30 kg/m). A further 40% and 30% of men and women, respectively, were overweight (BMI 25 to 30 kg/m). Increased WC (>102 for men and >88 cm for women) was recorded in 29% and 48%, CVD in 16% and 13%, and diabetes mellitus in 13% and 11% of men and women, respectively. A statistically significant graded increase existed in the frequency of CVD and diabetes mellitus with both BMI and WC, with a stronger relationship for WC than for BMI across regions for both genders. This relationship between WC, CVD, and particularly diabetes mellitus was seen even in lean patients (BMI<25 kg/m). CONCLUSIONS - Among men and women who consulted primary care physicians, BMI and particularly WC were both strongly linked to CVD and especially to diabetes mellitus. Strategies to address this global problem are required to prevent an epidemic of these major causes of morbidity and mortality. 2007 American Heart Association, Inc.
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Ng, Theodore W.K.; Watts, Gerald F.; Barrett, Hugh Hugh R.; Rye, Kerry Anne; Chan, Dick C.F.OBJECTIVE - The purpose of this study was to examine the effect of weight loss on LDL and HDL kinetics and plasma retinol-binding protein-4 (RBP-4) and adiponectin levels in men with the metabolic syndrome. RESEARCH DESIGN AND METHODS - LDL apolipoprotein (apo)B-100 and HDL apoA-I kinetics were studied in 35 obese men with the metabolic syndrome at the start and end of a 16-week intervention trial of a hypocaloric, low-fat diet (n = 20) versus a weight maintenance diet (n = 15) using a stable isotope technique and multicompartmental modeling. RESULTS - Consumption of the low-fat diet produced significant reductions (P < 0.01) in BMI, abdominal fat compartments, and homeostasis model assessment score compared with weight maintenance. These were associated with a significant increase in adiponectin and a fall in plasma RBP-4, triglycerides, LDL cholesterol, and LDL apoB-100 concentration (P < 0.05). Weight loss significantly increased the catabolism of LDL apoB-100 (+27%, P < 0.05) but did not affect production; it also decreased both the catabolic (-13%) and production (-13%) rates of HDL apoA-I (P < 0.05), thereby not altering plasma HDL apoA-I or HDL cholesterol concentrations. VLDL apoB-100 production fell significantly with weight loss (P < 0.05). The increase in LDL catabolism was inversely correlated with the fall in RBP-4 (r = -0.54, P <0.05) and the decrease in HDL catabolism with the rise in adiponectin (r = -0.56, P < 0.01). CONCLUSIONS - In obese men with metabolic syndrome, weight loss with a low-fat diet decreases the plasma LDL apoB-100 concentration by increasing the catabolism of LDL apoB-100; weight loss also delays the catabolism of HDL apoA-I with a concomitant reduction in the secretion of HDL apoA-I. These effects of weight loss could partly involve changes in RBP-4 and adiponectin levels. 2007 by the American Diabetes Association.
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Barter, Philip J.; Puranik, Rajesh; Rye, Kerry AnneSeveral known functions of high-density lipoproteins (HDLs) may contribute to their ability to protect against atherosclerosis. The best known of these functions is the ability to promote cholesterol efflux from cells in a process that may minimize the accumulation of foam cells in the artery wall. However, HDLs have additional properties, including antioxidant, anti-inflammatory, and antithrombotic effects, that may also be anti-atherogenic. Recent in vivo studies in several animal models have demonstrated that HDLs can inhibit acute and chronic vascular inflammation. The fact that these effects can be achieved with very low doses of reconstituted discoidal HDL or even lipid-free apolipoprotein A-I suggests that they may reflect activity of a minor, highly active HDL subpopulation. These results have potentially important clinical implications in regard to managing the acute vascular inflammation states that accompany acute coronary syndrome and acute ischemic stroke. Copyright 2007 by Current Medicine Group LLC.
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Orr, Yishay; Taylor, Jude Matthew; Cartland, Si; Bannon, Paul Gerard; Geczy, Carolyn L.; Kritharides, LeonardMembrane-activated complex 1 (Mac-1; CD11b/CD18) is a ?<inf>2</inf> integrin implicated in the pathophysiology of neutrophil-mediated tissue injury whose functional capacity is determined by stimulus-induced conformational activation rather than upregulation. Mac-1 up-regulation and conformational activation, together with shedding of L-selectin, are reported after in vitro neutrophil activation. However, their regulation on circulating human neutrophils during acute inflammation is unclear. Using flow cytometry, we investigated neutrophil expression of Mac-1, its activation-reporter neo-epitope CBRM1/5, and L-selectin during the inflammatory stimulus of cardiac surgery. A subpopulation of circulating neutrophils expressed CBRM1/5 (CBRM1/ 5+) under basal conditions (6.282.59%) and was persistently expanded (9.954.0%-15.24.2%; P<0.0001) peri-operatively, whereas total CD11b expression increased only transiently, intra-operatively. L-selectin expression was unchanged on CBRM1/5+ neutrophils, and soluble L-selectin levels decreased intra-operatively (P<0.01), indicating that L-selectin was not shed. Increased CBRM1/5 expression without L-selectin loss or CD11b up-regulation was replicated in vitro by neutrophil stimulation with IL-8, C3a, and platelet-activating factor. Heparin, a known CD11b ligand, which is administered during cardiac surgery, markedly reduced neutrophil expression of conformationally active CD11b in vivo and in vitro, identifying a potential mechanism for its anti-inflammatory properties. We conclude that conformational activation of CD11b occurs on circulating neutrophils in vivo and can occur in the absence of CD11b up-regulation and L-selectin shedding. Society for Leukocyte Biology.
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Barter, Philip J.; Caulfield, Mark J.; Eriksson, Mats; Grundy, Scott M.; Kastelein, Johannes Jacob Pieter; Komajda, Michel; Lez-Send, JosLu; Mosca, Lori J.; Tardif, Jean Claude; Waters, David D.; Shear, Charles L.; Revkin, James H.; Buhr, Kevin A.; Fisher, Marian R.; Tall, Alan R.; Brewer, BryanBackground: Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib. Methods: We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. Results: At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P<0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P = 0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P = 0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change. Conclusions: Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, NCT00134264.) Copyright 2007 Massachusetts Medical Society.
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Thompson, Simon R.; McCaskie, Pamela A.; Beilby, John P.; Hung, Joseph C.; Jennens, Michelle; Chapman, Caroline L.; Thompson, Peter Lindsay; Humphries, Steve EricBackground: Interleukin (IL)-18 is a proinflammatory cytokine that has been implicated in several diseases, including atherosclerosis, and increased circulating IL-18 concentrations increase risk of future coronary heart disease (CHD). We evaluated the effect of common variation within the IL18 gene on concentrations of circulating IL-18. Methods: We measured IL-18, by ELISA, in the population-based study group [Carotid Ultrasound Disease Assessment Study (CUDAS)] and a predominantly male cohort with premature cardiovascular disease [Carotid Ultrasound in Patients with Ischaemic Heart Disease (CUPID)]. Using a tagging single-nucleotide polymorphism (SNP) approach that captured >90% of genetic variation, we identified 4 common (>10%) haplotypes. Results: A common SNP was associated with differences in IL-18 concentrations; in CUDAS individuals carrying 2 copies of the rare allele, concentrations were 13% higher than in those with no copies (P = 0.002). Haplotypes were also associated with significant differences in IL-18 concentrations in CUDAS and CUPID. Haplotype GTATA (frequency 23%) was associated with significantly lower IL-18 than others. In CUDAS, those carrying 2 copies had IL-18 concentrations 15% lower than those carrying no copies (P = 0.002); in CUPID, the difference was 22% (P = 0.004). These associations remained significant after adjustment for age, sex, hypertension, HDL cholesterol, waist-to-hip ratio, and alcohol consumption. Despite being associated with differences in IL-18 concentrations, the haplotypes did not occur at different frequencies in those with or without carotid atherosclerotic plaques. Conclusions: Variation within IL18 affects IL-18 concentrations in healthy and diseased individuals and thus may influence the pathophysiology of plaques at all stages of CHD progression. 2007 American Association for Clinical Chemistry.
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Morgan, Philip E.; Sturgess, Allan D.; Hennessy, Annemarie; Davies, Michael J.Increased oxidative stress is a hallmark of the autoimmune disease systemic lupus erythematosus (SLE). This study compares serum protein oxidation levels in SLE patients without and with renal involvement (lupus nephritis); the latter have a significantly poorer prognosis. Similar increases in protein carbonyls and decreases in protein thiols were observed in both SLE groups compared to controls. Protein carbonyl distribution, determined by Western blotting of 2D gels, was similar in both SLE groups, suggesting factors other than oxidation also play a role in SLE complications. 2D electrophoresis examined the serum proteome further. Six proteins were significantly decreased in non-renal SLE patients compared to controls; five were identified by mass spectrometry, including one isoform of pro-atherogenic apoCIII. Total apoCIII levels (assessed by ELISA) in lupus nephritis patients were significantly elevated compared to controls or non-renal SLE patients. Thus, levels of oxidized proteins and apoCIII may be useful biomarkers in SLE studies.
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Skaff, Ojia; Pattison, David I.; Davies, Michael J.Hypohalous acids are generated from the oxidation of halide ions by myeloperoxidase and eosinophil peroxidase in the presence of H<inf>2</inf>O <inf>2</inf>. These oxidants are potent antibacterial agents, but excessive production can result in host tissue damage, with this implicated in a number of human pathologies. Rate constants for HOC1 with lipid components and antioxidants have been established. Here, the corresponding reactions of HOBr have been examined to determine whether this species shows similar reactivity. The second-order rate constants for the reaction of HOBr with 3-pentenoic acid and sorbate, models of unsaturated lipids, are 1.1 104 and 1.3 103 M-1 s-1, respectively, while those for reaction of HOBr with phosphoryl-serine and phosphoryl-ethanolamine are ca. 106 M-1 s-1. The second-order rate constants (M-1 s-1) for reactions of HOBr with Trolox (6.4 104), hydroquinone (2.4 105), and ubiquinol-0 (2.5 106) were determined, as models of the lipid-soluble antioxidants, ?-tocopherol, and ubiquinol-10; all of these rate constants are ca. 50-2000-fold greater than for HOCl. In contrast, the second-order rate constants for the reaction of HOBr with the water-soluble antioxidants, ascorbate and urate, are ca. 106 M-1 s -1 and closer in magnitude to those for HOCl. Kinetic models have been developed to predict the sites of HOBr attack on low-density lipoproteins. The data obtained indicate that HOBr reacts to a much greater extent with fatty acid side chains and lipid-soluble antioxidants than HOCl; this has important implications for HOBr-mediated damage to cells and lipoproteins. 2007 American Chemical Society.
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Cohn, Jeffrey S.[No abstract available]
