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Showing 1161–1180 of 2058 publications.
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Constantinides, Alexander; Kappelle, Paul Jan Willem Herman; Lambert, Gilles; Dullaart, Robin P.F.Background and Aims: Lipoprotein-associated phospholipase A <inf>2</inf> (Lp-PLA <inf>2</inf>) is a pro-atherogenic phospholipase A <inf>2</inf>, which is predominantly complexed to low-density lipoprotein (LDL) particles. Proprotein convertase subtilisin-kexin type 9 (PCSK9) provides a key step in LDL metabolism by stimulating LDL receptor degradation. We determined relationships between plasma PCSK9 and Lp-PLA <inf>2</inf> mass. Methods: Lp-PLA <inf>2</inf> mass (turbidimetric immunoassay), PCSK9 (enzyme-linked immunosorbent assay) and (apo) lipoproteins were measured in 53 nondiabetic subjects (27 women) with body mass index <30 kg/m 2. Results: Lp-PLA <inf>2</inf> and PCSK9 levels were both correlated positively with LDL cholesterol and non-high-density lipoprotein (HDL) cholesterol (r = 0.330 to r = 0.382, p ?0.02). Remarkably, Lp-PLA <inf>2</inf> was inversely related to PCSK9 (r = -0.388, p = 0.004). The Lp-PLA <inf>2</inf>/apolipoprotein B ratio, as a measure of the Lp-PLA <inf>2</inf> content in apolipoprotein B-containing lipoproteins, was also inversely correlated with PCSK9 (r = -0.575, p <0.001). The inverse relationships of Lp-PLA <inf>2</inf> (p = 0.023) and the Lp-PLA <inf>2</inf>/apolipoprotein B ratio (p = 0.001) with PCSK9 levels remained significant after controlling for age, gender, triglycerides and HDL cholesterol. Conclusions: Despite increasing effects on LDL cholesterol, higher PCSK9 levels are unlikely to confer impaired Lp-PLA <inf>2</inf> metabolism. We propose to evaluate the possible influence of PCSK9 inhibiting strategies on Lp-PLA <inf>2</inf> regulation and vice versa to determine effects of Lp-PLA <inf>2</inf> inhibitors on the PCSK9 pathway. 2012 IMSS.
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Marshall, Nathaniel S.; Ayer, Julian Ganesh J.; Toelle, Brett G.; Phillips, Craig L.; Grunstein, Ronald R.; Celermajer, David S.; Marks, Guy B.[No abstract available]
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Skaff, Ojia; Pattison, David I.; Morgan, Philip E.; Bachana, Rushad; Jain, Vimal Kumar; Priyadarsini, K. I.; Davies, Michael J.Elevated MPO (myeloperoxidase) levels are associated with multiple human inflammatory pathologies. MPO catalyses the oxidation of Cl -, Br - and SCN - by H <inf>2</inf>O <inf>2</inf> to generate the powerful oxidants hypochlorous acid (HOCl), hypobromous acid (HOBr) and hypothiocyanous acid (HOSCN) respectively. These species are antibacterial agents, but misplaced or excessive production is implicated in tissue damage at sites of inflammation. Unlike HOCl and HOBr, which react with multiple targets, HOSCN targets cysteine residues with considerable selectivity. In the light of this reactivity, we hypothesized that Sec (selenocysteine) residues should also be rapidly oxidized by HOSCN, as selenium atoms are better nucleophiles than sulfur. Such oxidation might inactivate critical Sec-containing cellular protective enzymes such as GPx (glutathione peroxidase) and TrxR (thioredoxin reductase). Stopped-flow kinetic studies indicate that seleno-compounds react rapidly with HOSCN with rate constants, k, in the range 2.8 10 3-5.8 10 6 M -1s -1(for selenomethionine and selenocystamine respectively). These values are ?6000-fold higher than the corresponding values for H <inf>2</inf>O <inf>2</inf>, and are also considerably larger than for the reaction of HOSCN with thiols (16-fold for cysteine and 80-fold for selenocystamine). Enzyme studies indicate that GPx and TrxR, but not glutathione reductase, are inactivated by HOSCN in a concentration-dependent manner; k for GPx has been determined as ?5 10 5 M -1s -1. Decomposed HOSCN did not induce inactivation. These data indicate that selenocysteine residues are oxidized rapidly by HOSCN, with this resulting in the inhibition of the critical intracellular Sec-dependent protective enzymes GPx and TrxR. 2011 The Author(s).
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Pattison, David I.; Rahmanto, Aldwin Suryo; Davies, Michael J.Photo-induced damage to proteins occurs via multiple pathways. Direct damage induced by UVB (? 280-320 nm) and UVA radiation (? 320-400 nm) is limited to a small number of amino acid residues, principally tryptophan (Trp), tyrosine (Tyr), histidine (His) and disulfide (cystine) residues, with this occurring via both excited state species and radicals. Indirect protein damage can occur via singlet oxygen (1O<inf>2</inf> 1?<inf>g</inf>), with this resulting in damage to Trp, Tyr, His, cystine, cysteine (Cys) and methionine (Met) residues. Although initial damage is limited to these residues multiple secondary processes, that occur both during and after radiation exposure, can result in damage to other intra- and inter-molecular sites. Secondary damage can arise via radicals (e.g. Trp, Tyr and Cys radicals), from reactive intermediates generated by 1O<inf>2</inf> (e.g. Trp, Tyr and His peroxides) and via molecular reactions of photo-products (e.g. reactive carbonyls). These processes can result in protein fragmentation, aggregation, altered physical and chemical properties (e.g. hydrophobicity and charge) and modulated biological turnover. Accumulating evidence implicates these events in cellular and tissue dysfunction (e.g. apoptosis, necrosis and altered cell signaling), and multiple human pathologies.
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Zhang, Lei; Yan, Feng; Zhang, Shengli; Lei, Dongsheng; Charles, Merle Arthur; Cavigiolio, Giorgio; Oda, Michael N.; Krauss, Ronald M.; Weisgraber, Karl H.; Rye, Kerry Anne; Pownall, Henry J.; Qiu, Xiayang; Ren, GangHuman cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl ester mass from atheroprotective high-density lipoproteins to atherogenic low-density lipoproteins by an unknown mechanism. Delineating this mechanism would be an important step toward the rational design of new CETP inhibitors for treating cardiovascular diseases. Using EM, single-particle image processing and molecular dynamics simulation, we discovered that CETP bridges a ternary complex with its N-terminal ?-barrel domain penetrating into high-density lipoproteins and its C-terminal domain interacting with low-density lipoprotein or very-low-density lipoprotein. In our mechanistic model, the CETP lipoprotein-interacting regions, which are highly mobile, form pores that connect to a hydrophobic central cavity, thereby forming a tunnel for transfer of neutral lipids from donor to acceptor lipoproteins. These new insights into CETP transfer provide a molecular basis for analyzing mechanisms for CETP inhibition. 2012 Nature America, Inc. All rights reserved.
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Watts, Gerald F.; Sullivan, David R.; Poplawski, Nicola Kazia; van Bockxmeer, Frank M.; Hamilton-Craig, I. R.; Clifton, P. M.; OBrien, Richard C.; Bishop, Warrick L.J.; George, Peter Myles; Barter, Philip J.; Bates, Timothy R.; Burnett, John R.; Coakley, John C.; Davidson, Patricia Mary; Emery, Jon David; Martin, Andrew C.; Farid, Waleed; Freeman, Lucinda; Geelhoed, Elizabeth A.; Juniper, Amanda; Kidd, Alexa M.J.; Kostner, Karam Maximilien; Krass, Ines; Livingston, Michael; Maxwell, Suzy; O'Leary, Peter C.; Owaimrin, Amal; Redgrave, Trevor G.; Reid, Nicola J.; Southwell, Lynda; Suthers, Graeme Kemble; Tonkin, Andrew Maxwell; Towler, Simon C.B.; Trent, Ronald J.A.Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remains undetected and those diagnosed with the condition are inadequately treated.To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensus model of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a wide spectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoC aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes.The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis, assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbone for detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol risk factors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are given for genetic testing. An integrative system for providing best clinical care is described.This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources. After initial implementation, the MoC will require critical evaluation, development and appropriate modification. 2011 Elsevier Ireland Ltd.
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Ayer, Julian Ganesh J.; Belousova, Elena G.; Harmer, Jason A.; Toelle, Brett G.; Celermajer, David S.; Marks, Guy B.Background: In older adults, an independent association exists between impaired lung function and cardiovascular disease. This interaction might be related to the effects of aging and/or smoking. In order to explore possible childhood antecedents to this association, we hypothesized that decreased lung function and vascular stiffness might be related, in early life. Objective: To determine the relationship between lung function and carotid augmentation index (AIx), a measure of vascular stiffness, in 8-year old children. Methods: Data on brachial blood pressure, lung function (FEV <inf>1</inf>, FVC, FEV <inf>1</inf>/FVC, obtained by spirometry) and carotid AIx75 (AIx standardised to an arbitrary heart rate of 75 beats per minute, obtained by applanation tonometry) was available in 249 community-based 8-year old children. These healthy children had been subjects in a randomised controlled trial of two interventions (omega-3 fatty acid supplementation and house-dust mite avoidance) to prevent asthma. Smoking in pregnancy and childhood environmental tobacco smoke (ETS) exposure was prospectively collected by questionnaire. The association between lung function and carotid AIx75 was assessed in multivariate models that included sex, height, smoking status during pregnancy, ETS exposure and randomisation groups (house dust mite avoidance and dietary intervention) as covariates. Results: In the fully adjusted models, Carotid AIx75 was independently associated with FEV1 (standardised ? = -0.17,b = -6.72, partial R 2 =. 02, p = 0.03), FVC (standardised ? = -0.29, b = -9.31, partial R 2 = 0.04, p<0.001) and FEV1/FVC (standardised ? =. 13, b = 18.4, partial R 2 = 0.02, p = 0.04). Conclusion: Lower lung volumes are associated with increased vascular stiffness at an early age. The interaction between lung function and vascular stiffness may thus represent more than just age-related alterations in both the pulmonary and vascular systems. 2011 Ayer et al.
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Sunderland, Neroli; Thomson, Sally E.; Heffernan, Scott J.; Lim, Shirlene M.; Thompson, John F.; Ogle, Robert F.; McKenzie, Paul R.; Kirwan, Paul D.; Makris, Angela; Hennessy, AnnemariePreeclampsia is a common disease of pregnancy characterised by maternal hypertension and proteinuria. Abnormal placentation in early pregnancy and abnormal cytokine and anti-angiogenic factor expression are thought to contribute to the clinical syndrome of endothelial dysfunction evident in the second half of gestation. The mechanisms underlying both the placental pathology and its translation to the maternal clinical syndrome are not fully understood. A model of preeclampsia manifest by clinically evident endothelial dysfunction (increased blood pressure and proteinuria) was induced by administration of low-dose TNF-? for 2. weeks at mid-gestation in pregnant baboons (Papio hamadryas). Blood pressure was monitored continuously and remotely by intra-arterial radiotelemetry. Following TNF-? infusion, there was an increase in systolic and diastolic blood pressure and development of proteinuria in pregnant treated animals, but not in pregnant saline controls nor in non-pregnant TNF-? treated animals. The treated pregnant animals also developed elevated plasma soluble FMS-like tyrosine kinase-1 (sFLT-1) and increased placental mRNA expression of sFLT-1 and soluble endoglin (sEng). These results clearly demonstrate that the cytokine TNF-? can induce the clinical and biochemical features of human preeclampsia. The results identify a link between cytokines, placental dysfunction and endothelial dysfunction resulting in a loss of maternal blood pressure control. 2011 Elsevier Ltd.
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Morgan, Philip E.; Pattison, David I.; Talib, Jihan; Summers, Fiona A.; Harmer, Jason A.; Celermajer, David S.; Hawkins, Clare L.; Davies, Michael J.Smokers have an elevated risk of atherosclerosis but the origins of this elevated risk are incompletely defined, though evidence supports an accumulation of the oxidant-generating enzyme myeloperoxidase (MPO) in the inflamed artery wall. We hypothesized that smokers would have a high level of thiocyanate (SCN -), a preferred substrate for MPO, which in turn would predispose to thiol oxidation, an established independent risk factor for atherosclerosis. In this study it is shown that on exposure to MPO/H <inf>2</inf>O <inf>2</inf>, thiols on plasma proteins from nonsmokers were increasingly oxidized with increasing added SCN - concentrations. Plasma from smokers contained significantly higher endogenous levels of SCN - than that from nonsmokers (131 31 vs 40 24 ?M, P < 0.0001). When plasma from smokers and nonsmokers was exposed to MPO/H <inf>2</inf>O <inf>2</inf>-stimulated oxidation, a strong positive correlation (r = 0.8139, P < 0.0001) between the extent of thiol oxidation and the plasma SCN - concentrations was observed. Computational calculations indicate a changeover from HOCl to HOSCN as the major MPO-generated oxidant in plasma, with increasing SCN - levels. These data indicate that plasma SCN - levels are a key determinant of the extent of thiol oxidation on plasma proteins induced by MPO, and implicate HOSCN as an important mediator of inflammation-induced oxidative damage to proteins in smokers. 2011 Elsevier Inc.
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Barter, Philip J.Evidence that low-density lipoprotein-cholesterol (LDL-C) causes cardiovascular disease (CVD) is overwhelming. It has also been proven beyond all doubt that lowering the level of LDL-C using statins reduces CV risk. However, many people remain at high risk even when their level of LDL-C has been reduced by aggressive treatment with statins. One reason for this residual risk can be a low level of high-density lipoprotein-cholesterol (HDL-C).The concentration of HDL-C is an independent, inverse predictor for CVD. This relationship is apparent even when treatment with statins has reduced the level of LDL-C to below 1.8 mmol/L (70 mg/dL). It has therefore been suggested that raising the level of HDL-C should be considered as a therapeutic strategy for reducing the residual CV risk that persists in some people, despite aggressive LDL-C lowering with statins. HDL particles have several functions with the potential to protect against arterial disease, the best known of which relates to their ability to promote cholesterol efflux from macrophages in the artery wall. However, HDLs have several additional protective properties that are independent of their involvement in cholesterol metabolism. For example, they have properties that reduce oxidation, vascular inflammation and thrombosis, improve endothelial function, promote endothelial repair, enhance insulin sensitivity and promote insulin secretion by pancreatic beta islet cells. There is also a large and compelling body of evidence in animal models showing that interventions that increase HDL levels are profoundly anti-atherogenic. Major causes of low HDL are abdominal obesity and type 2 diabetes, the worldwide incidences of which are increasing at alarming rates. Strategies to increase the concentration of HDL should begin with lifestyle changes such as weight reduction, increased physical activity and smoking cessation. However, compliance with such measures is frequently poor and pharmacological intervention may be required. Currently available HDL-raising medications include fibrates, niacin and statins. There is indisputable evidence that lowering LDL-C levels using statins translates into a large reduction in CV risk. There is also mounting evidence that increasing the level of HDL-C using statins contributes to an additional reduction in CV risk. For example, the increase in HDL-C levels that was associated with simvastatin treatment in the 4S study was a significant predictor for the reduction in CV events. Moreover, a meta-analysis of 1,455 patients in 4 coronary intravascular ultrasound imaging trials showed that both the achieved level of LDL-C and the increase in HDL-C concentration during statin treatment were significant independent predictors for coronary atheroma progression as assessed by coronary intravascular ultrasound. In conclusion, evidence suggests that low levels of HDL-C are associated with an increased CV risk even when LDL-C is reduced to below 1.7 mmol/L (70 mg/dL) with a statin. Moreover, there is mounting evidence that increasing the level of HDL-C has the capacity to reduce CV risk. Thus, there is a compelling case for targeting both the LDL and HDL fractions to reduce CV risk in people with dyslipidemia, high CV risk and low levels of HDL-C. 2011 Elsevier Ireland Ltd.
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Barter, Philip J.Lowering low-density lipoprotein-cholesterol (LDL-C) levels using statins can significantly reduce cardiovascular (CV) risk in patients with dyslipidemia. However, the risk of major vascular events in those attaining the maximum levels of LDL-C-reduction is only reduced by around one third, which leaves a substantial residual risk. The Emerging Risk Factors Collaboration has shown that low levels of high-density lipoprotein-C (HDL-C) are independent risk factors for CV disease. It is therefore important that treatment strategies for dyslipidemia should target HDL-C in addition to LDL-C. Raising HDL-C can be achieved by both lifestyle changes and pharmacological means. Therapeutic strategies include niacin, fibrates, thiazolidinediones, apolipoprotein A1 mimetics, cholesteryl ester transfer protein inhibitors, statins and combinations thereof. In general, statins produce inconsistent increases in HDL-C. However, pitavastatin, a new member of the statin family that was launched in 2003, and rosuvastatin consistently elicit marked increases in HDL-C that are sustained over time. This supplement will discuss the contribution of HDL-C as a possible predictor and modifiable risk factor for CV disease and will examine the potential role for pitavastatin in reducing residual CV risk. 2011 Elsevier Ireland Ltd. All rights reserved.
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Klop, Boudewijn; Cohn, Jeffrey S.; van Oostrom, Antonie J.H.H.M.; van Wijk, Jeroen P.H.; Birnie, Erwin; Castro-Cabezas, Manuel C.Background: Triglyceride (TG) levels measured in either the fasting or non-fasting state predict the risk of cardiovascular disease (CVD). Since CVD risk assessment is affected by variability in TG, the aim of the study was to investigate intra-individual variability of non-fasting TG. Methods: Capillary triglyceride (cTG) levels were measured in 246 free-living individuals at six time-points during the day on three separate occasions. Intra-individual variability in cTG was assessed by calculating the standard deviation of three measures at each time-point. Subjects were analyzed by gender and by fasting TG level. Results: In the fasting state, intra-individual variability was similar in males and females (0.28 and 0.35. mmol/l, respectively), but increased significantly in male but not in female subjects during the day, i.e., 0.28 to 0.69, and 0.35 to 0.36. mmol/l, resp. Subjects with higher fasting TG levels had greater absolute variability in both fasting and non-fasting TG. Conclusions: The variability in non-fasting TG is greater in males and in individuals with higher levels of TG. Since greatest variability in non-fasting TG occurs very late in the day, it is unlikely to affect the assessment of CVD risk, which is based on a blood sample taken during daylight hours. 2011 Elsevier B.V.
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Moheimani, Fatemeh; Tan, Joanne Tsui Ming; Brown, Bronwyn E.; Heather, Alison Kay; Van Reyk, David M.; Davies, Michael J.During atherosclerosis monocyte-derived macrophages accumulate cholesteryl esters from low-density lipoproteins (LDLs) via lectin-like oxidised LDL receptor-1 (LOX-1) and class AI and AII (SR-AI, SR-AII) and class B (SR-BI, CD36) scavenger receptors. Here we examined the hypothesis that hyperglycaemia may modulate receptor expression and hence lipid accumulation in macrophages. Human monocytes were matured into macrophages in 30 versus 5mM glucose and receptor expression and lipid accumulation quantified. High glucose elevated LOX1 mRNA, but decreased SR-AI, SR-BI, LDLR, and CD36 mRNA. SR-BI and CD36 protein levels were decreased. Normo- and hyperglycaemic cells accumulated cholesteryl esters from modified LDL to a greater extent than control LDL, but total and individual cholesteryl ester accumulation was not affected by glucose levels. It is concluded that, whilst macrophage scavenger receptor mRNA and protein levels can be modulated by high glucose, these are not key factors in lipid accumulation by human macrophages under the conditions examined. Copyright 2011 Fatemeh Moheimani et al.
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Dunlop, Rachael Anne[No abstract available]
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Relationship of plasma interleukin-6 and its genetic variants with hypertension in Hong Kong chineseCheung, Bernard Man Yung; Ong, Kwok Leung; Tso, Annette Wai Kwan; Leung, Raymond Y.H.; Cherny, Stacey S.; Sham, Pak Chung; Neil Thomas, Graham Neil; Lam, Tai Hing; Lam, Karen Siu LingBackground Interleukin-6 (IL6) plays a central role in inflammation, insulin resistance, and atherogenesis. We investigated the associations of plasma IL6 and its genetic variants with hypertension in both cross-sectional and prospective study designs. Methods Plasma IL6 was measured in 648 normotensive and 294 hypertensive subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS)-2 in 2000-2004 and three tagging single-nucleotide polymorphisms (SNPs) in the IL6 gene were genotyped. Among subjects normotensive in CRISPS-2 (baseline), 515 subjects were followed-up in CRISPS-3 in 2005-2008 and 100 of them had developed hypertension. Results At baseline, plasma IL6 correlated with systolic blood pressure (SBP) (r = 0.128, P < 0.001). Hypertensive subjects had significantly higher plasma IL6 after adjusting for age and sex (geometric mean (95% confidence interval (CI) = 0.60 (0.54-0.65) vs. 0.47 (0.44-0.50) ng/l, P = 0.021). In multiple logistic regression, higher plasma IL6 was associated with hypertension in women (P = 0.009), but not in men. The minor G allele of SNP rs1800796 was associated with lower plasma IL6 (geometric mean (95% CI) = 0.46 (0.41-0.51) ng/l for CG and 0.49 (0.39-0.62) ng/l for GG vs. 0.53 (0.50-0.57) ng/l for CC, P = 0.005). However, this SNP was not associated with hypertension or blood pressure at baseline. Among subjects normotensive in CRISPS-2, plasma IL6 was not associated with the development of hypertension in CRISPS-3. Conclusion The SNP rs1800796 affected plasma IL6 with a small effect size. Elevated plasma IL6 is associated with prevalent hypertension in women, but not incident hypertension. 2011 American Journal of Hypertension, Ltd.
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Barter, Philip J.; Rye, Kerry AnneElevated low-density lipoprotein-cholesterol (LDL-C) and reduced high-density lipoprotein-cholesterol (HDL-C) are major risk factors for the development of cardiovascular disease. One approach to raising HDL-C is to inhibit the cholesteryl ester transfer protein (CETP), a plasma protein that promotes transfer of cholesteryl esters from HDL and other lipoprotein fractions. Drugs that inhibit CETP increase HDL-C and some lower LDL-C. However, the development of torcetrapib, the first CETP inhibitor to be tested in a human clinical outcomes trial, was terminated because it caused an excess of deaths and cardiovascular events. There is evidence, however, that torcetrapib had adverse off-target effects unrelated to CETP inhibition. This has opened the way for retesting of the hypothesis that CETP inhibitors will be anti-atherogenic in studies conducted with agents such as dalcetrapib and anacetrapib that do not share the off-target effects of torcetrapib. Clinical outcome trials with dalcetrapib and anacetrapib are currently under way. 2011 Elsevier Ltd. All Rights Reserved.
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Di Bartolo, Belinda Ann; Vanags, Laura Z.; Tan, Joanne Tsui Ming; Bao, Shishan San; Rye, Kerry Anne; Barter, Philip J.; Bursill, C. A.High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties. The development of peptides that mimic HDL apolipoproteins offers a promising strategy to reduce inflammatory disease. This study aimed to compare the anti-inflammatory effects of ETC-642, an apoA-I mimetic peptide, with that of discoidal reconstituted HDL (rHDL), consisting of full-length apoA-I complexed with phosphatidylcholine, in rabbits with chronic vascular inflammation. New Zealand White rabbits (n = 10/group) were placed on chow supplemented with 0.2% (w/w) cholesterol for 6-weeks. The animals received two infusions of saline, rHDL (8 mg/kg apoA-I) or ETC-642 (30 mg/kg peptide) on the third and fifth days of the final week. The infusions of rHDL and ETC-642 were able to significantly reduce cholesterol-induced expression of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the thoracic aorta (p < 0.05). When isolated rabbit HDL was pre-incubated with human coronary artery endothelial cells (HCAECs), prior to stimulation with TNF-?, it was found that HDL from ETC-642 treated rabbits were more effective at inhibiting the TNF-?-induced increase in ICAM-1, VCAM-1 and p65 than HDL isolated from saline treated rabbits (p < 0.05). There were, however, no changes in HDL lipid composition between treatment groups. Infusion of ETC-642 causes anti-inflammatory effects that are comparable to rHDL in an animal model of chronic vascular inflammation and highlights that apoA-I mimetic peptides present a viable strategy for the treatment of inflammatory disease.
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Nicholls, Stephen J.; Ballantyne, Christie Mitchell; Barter, Philip J.; Chapman, Martin John; ERBEL, RAIMUND; Libby, Peter A.; Raichlen, Joel S.; Uno, Kiyoko; Borgman, Marilyn R.N.; Wolski, Kathy E.; Nissen, Steven E.Background: Statins reduce adverse cardiovascular outcomes and slow the progression of coronary atherosclerosis in proportion to their ability to reduce low-density lipoprotein (LDL) cholesterol. However, few studies have either assessed the ability of intensive statin treatments to achieve disease regression or compared alternative approaches to maximal statin administration. Methods: We performed serial intravascular ultrasonography in 1039 patients with coronary disease, at baseline and after 104 weeks of treatment with either atorvastatin, 80 mg daily, or rosuvastatin, 40 mg daily, to compare the effect of these two intensive statin regimens on the progression of coronary atherosclerosis, as well as to assess their safety and side-effect profiles. Results: After 104 weeks of therapy, the rosuvastatin group had lower levels of LDL cholesterol than the atorvastatin group (62.6 vs. 70.2 mg per deciliter [1.62 vs. 1.82 mmol per liter], P<0.001), and higher levels of high-density lipoprotein (HDL) cholesterol (50.4 vs. 48.6 mg per deciliter [1.30 vs. 1.26 mmol per liter], P = 0.01). The primary efficacy end point, percent atheroma volume (PAV), decreased by 0.99% (95% confidence interval [CI], -1.19 to -0.63) with atorvastatin and by 1.22% (95% CI, -1.52 to -0.90) with rosuvastatin (P = 0.17). The effect on the secondary efficacy end point, normalized total atheroma volume (TAV), was more favorable with rosuvastatin than with atorvastatin: -6.39 mm3 (95% CI, -7.52 to -5.12), as compared with -4.42 mm3 (95% CI, -5.98 to -3.26) (P = 0.01). Both agents induced regression in the majority of patients: 63.2% with atorvastatin and 68.5% with rosuvastatin for PAV (P = 0.07) and 64.7% and 71.3%, respectively, for TAV (P = 0.02). Both agents had acceptable side-effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events. Conclusions: Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Despite the lower level of LDL cholesterol and the higher level of HDL cholesterol achieved with rosuvastatin, a similar degree of regression of PAV was observed in the two treatment groups. (Funded by AstraZeneca Pharmaceuticals; ClinicalTrials.gov number, NCT000620542.). Copyright 2011 Massachusetts Medical Society.
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Ong, Kwok Leung; Barter, Philip J.; Rye, Kerry Anne[No abstract available]
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Rahmanto, Aldwin Suryo; Davies, Michael J.Selenium is a critical trace element, with deficiency associated with numerous diseases including cardiovascular disease, diabetes, and cancer. Selenomethionine (SeMet; a selenium analogue of the amino acid methionine, Met) is a major form of organic selenium and an important dietary source of selenium for selenoprotein synthesis in vivo. As selenium compounds can be readily oxidized and reduced, and selenocysteine residues play a critical role in the catalytic activity of the key protective enzymes glutathione peroxidase and thioredoxin reductase, we investigated the ability of SeMet (and its sulfur analogue, Met) to scavenge hydroperoxides present on amino acids, peptides, and proteins, which are key intermediates in protein oxidation. We show that SeMet, but not Met, can remove these species both stoichiometrically and catalytically in the presence of glutathione (GSH) or a thioredoxin reductase (TrxR)/thioredoxin (Trx)/NADPH system. Reaction of the hydroperoxide with SeMet results in selenoxide formation as detected by HPLC. Recycling of the selenoxide back to SeMet occurs rapidly with GSH, TrxR/NADPH, or a complete TrxR/Trx/NADPH reducing system, with this resulting in an enhanced rate of peroxide removal. In the complete TrxR/Trx/NADPH system loss of peroxide is essentially stoichiometric with NADPH consumption, indicative of a highly efficient system. Similar reactions do not occur with Met under these conditions. Studies using murine macrophage-like J774A.1 cells demonstrate a greater peroxide-removing capacity in cells supplemented with SeMet, compared to nonsupplemented controls. Overall, these findings demonstrate that SeMet may play an important role in the catalytic removal of damaging peptide and protein oxidation products. 2011 Elsevier Inc. All rights reserved.
