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Showing 1121–1140 of 2058 publications.
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Rye, Kerry Anne; Barter, Philip J.[No abstract available]
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Chen, Cheng; Tso, Annette Wai Kwan; Cheung, Bernard Man Yung; Law, Lawrence Siu Chun; Ong, Kwok Leung; Wat, Nelson Ming Sang; Janus, Edward Denis; Xu, Aimin; Lam, Karen Siu LingObjectives: Pigment epithelium-derived factor (PEDF) is secreted from the adipose tissue. It circulates at high concentrations, and was reported to play a causal role in obesity-induced insulin resistance and metabolic dysfunctions in mice. Previous cross-sectional studies also demonstrated plasma PEDF concentration correlated positively with systolic blood pressure (BP) and pulse pressure, and inversely with small artery elasticity. Here we investigated the relationship of plasma PEDF concentration with BP and incident hypertension in a 10-year prospective study. Methods: Baseline plasma PEDF concentrations were measured by ELISA in 520 Chinese subjects, aged 51 12 years, followed up long-term from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study. The association between plasma PEDF concentration and BP was investigated in both cross-sectional and prospective studies, using multiple linear regression and path analyses. Cox proportional hazards analysis was used to determine whether baseline PEDF concentration was independently related to the subsequent development of hypertension over 10 years. Results: Baseline plasma concentrations of PEDF were higher in men (P < 0.001), and were directly related to systolic BP at 2 and 5 years, and to diastolic BP at 2 years, after adjustment for covariates. Of the 386 normotensive subjects at baseline, high baseline PEDF concentration was predictive of incident hypertension, independent of the effects of age, sex, baseline BP and obesity parameters (hazard ratio: 1.135; 95% CI: 1.039-1.241; P = 0.005). Conclusion: Our data suggest that plasma PEDF concentration is significantly associated with BP, and incident hypertension. PEDF may be involved in the pathogenesis of hypertension in humans. 2012 Blackwell Publishing Ltd.
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Samaranayake, N. R.; Ong, Kwok Leung; Leung, Raymond Y.H.; Cheung, Bernard Man YungPurpose: The prevalence of obesity has been increasing in the United States. We set out to investigate the use of pharmacologic and non-pharmacologic therapy for the treatment of obesity in recent years. Methods: We included 2630 men and 2702 women who took part in the National Health and Nutrition Examination Survey from 2007 to 2008. We analyzed their demographic and anthropometric data and their weight and drug history. Results: A total of 45.9% of men and 45.0% of women were candidates for treatment (body mass index ?30 kg/m 2, or ?27 kg/m 2 with risk factors). Among these participants, 85.1% considered themselves overweight, 90.1% would like to lose weight, 61.9% had dietary changes, 36.5% exercised, 3.7% took nonprescription drugs, and 2.2% took prescription drugs to control weight during the preceding year. During the preceding month, 0.5% and 0.1% of participants were taking phentermine and orlistat, respectively. There were no participants on sibutramine. Conclusions: Although obesity is highly prevalent, only a small percentage of obese Americans are on anti-obesity medication. The withdrawal of sibutramine would have minimal impact on the general population. There is a need for more lifestyle changes in the majority of obese individuals. 2012 Elsevier Inc.
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Huijgen, Roeland; Fouchier, Sigrid W.; Denoun, Marc Ben; Hutten, Barbara A.; Vissers, Maud N.; Lambert, Gilles; Kastelein, Johannes Jacob PieterThe extent of hypercholesterolemia varies considerably in patients with familial hypercholesterolemia (FH). We hypothesized that the variability of the FH phenotype might be partly explained by variation in proprotein convertase subtilisin kexin type 9 (PCSK9) activity. Individuals between 18 and 53 years of age who had been tested for a pathogenic LDLR or APOB mutation were eligible. Mutation carriers with a LDL-C level below the 75 th percentile (called "FH low") were selected, as well as those with LDL-C above the 90 th percentile (called "FH high"). Relatives who tested negative for the mutation were the "controls." PCSK9 plasma levels were assessed in 267 individuals who did not receive cholesterol-lowering treatment at the time of the study. Mean PCSK9 plasma levels (95% CI) were lower in the FH-low group compared with the FH-high group [152 (137-167) ng/ml vs. 186 (165-207) ng/ml, P = 0.010] and the control group [177 (164-190) ng/ml, P = 0.013]. Mean PCSK9 levels did not statistically differ between the FH-high and control groups ( P = 0.50). Plasma PCSK9 levels are positively associated with LDL-C levels in FH patients and might contribute to the phenotypic severity in this disorder. Therefore, the results of pharmaceutical inhibition of PCSK9 in FH patients are eagerly awaited. Copyright 2012 by the American Society for Biochemistry and Molecular Biology, Inc.
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Tso, Colin; Rye, Kerry Anne; Barter, Philip J.Objective: Blood monocytes are known to express endothelial-like genes during co-culture with endothelium. In this study, the time-dependent change in the phenotype pattern of primary blood monocytes after adhering to endothelium is reported using a novel HLA-A2 mistyped co-culture model. Methods and Results: Freshly isolated human PBMCs were co-cultured with human umbilical vein endothelial cells or human coronary arterial endothelial cells of converse human leukocyte antigen A2 (HLA-A2) status. This allows the tracking of the PBMC-derived cells by HLA-A2 expression and assessment of their phenotype pattern over time. PBMCs that adhered to the endothelium at the start of the co-culture were predominantly CD11b+ blood monocytes. After 24 to 72 hours in co-culture, the endothelium-adherent monocytes acquired endothelial-like properties including the expression of endothelial nitric oxide synthase, CD105, CD144 and vascular endothelial growth factor receptor 2. The expression of monocyte/ macrophage lineage antigens CD14, CD11b and CD36 were down regulated concomitantly. The adherent monocytes did not express CD115 after 1 day of co-culture. By day 6, the monocyte-derived cells expressed vascular cell adhesion molecule 1 in response to tumour necrosis factor alpha. Up to 10% of the PBMCs adhered to the endothelium. These monocyte-derived cells contributed up to 30% of the co-cultured cell layer and this was dose-dependent on the PBMC seeding density. Conclusions: Human blood monocytes undergo rapid phenotype change to resemble endothelial cells after adhering to endothelium. 2012 Tso et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Huijgen, Roeland; Boekholdt, S. M.; Arsenault, Beno J.; Bao, Weihang; Davaine, Jean Michel; Tabet, Fatiha; Petrides, Francine; Rye, Kerry Anne; DeMicco, David A.; Barter, Philip J.; Kastelein, Johannes Jacob Pieter; Lambert, GillesObjectives: The purpose of this study was to investigate whether high levels of circulating proprotein convertase subtilisin kexin type 9 (PCSK9) would increase cardiovascular risk in statin-treated patients. Background: Statins activate low-density lipoprotein (LDL) receptor gene expression, thus lowering plasma LDL levels. But statins also activate the expression of PCSK9, a secreted inhibitor of the LDL receptor, thereby limiting their beneficial effects. Methods: We have measured the plasma PCSK9 levels of 1,613 patients with stable coronary heart disease enrolled in the Treating to New Targets study, a randomized trial that compared the efficacy of high- versus low-dose atorvastatin. After a run-in period with atorvastatin 10 mg daily, patients were randomized to either continue with 10 mg or be up-titrated to 80 mg of atorvastatin, and followed during 5 years for major cardiovascular events (MCVEs). Results: Circulating PCSK9 levels measured at randomization were predictive of clinical outcomes in the group randomized to remain on atorvastatin 10 mg (p = 0.039), but not in the group that intensified atorvastatin treatment to 80 mg (p = 0.24). Further, PCSK9 levels measured 1 year post-randomization did not change upon increase of the statin dose. Conclusions: PCSK9 levels predict cardiovascular events in patients treated with low-dose atorvastatin. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691) 2012 American College of Cardiology Foundation.
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Boon, Ai Ching; Hawkins, Clare L.; Bisht, Kavita; Coombes, Jeff S.; Bakrania, Bhavisha A.; Wagner, Karl Heinz; Bulmer, Andrew CameronA protective association between bilirubin and atherosclerosis/ischemic heart disease clearly exists in vivo. However, the relationship between bilirubin and in vivo oxidative stress parameters in a clinical population remains poorly described. The aim of this study was to assess whether persons expressing Gilbert syndrome (GS; i.e., unconjugated hyperbilirubinemia) are protected from thiol oxidation and to determine if this, in addition to their improved lipoprotein profile, could explain reduced oxidized low-density lipoprotein (oxLDL) status in them. Forty-four matched GS and control subjects were recruited and blood was prepared for the analysis of lipid profile and multiple plasma antioxidants and measures of oxidative stress. GS subjects possessed elevated plasma reduced thiol (8.031.09 versus 6.751.39 nmol/mg protein; P<0.01) and glutathione concentrations (12.72.39 versus 9.442.45 ?M; P<0.001). Oxidative stress status (reduced:oxidized glutathione; GSH:GSSG) was significantly improved in GS (0.490.16 versus 0.320.12; P<0.001). Protein carbonyl concentrations were negatively associated with bilirubin concentrations and were significantly lower in persons with >40 ?M bilirubin versus controls (<17.1 ?mol/L; P<0.05). Furthermore, absolute oxLDL concentrations were significantly lower in GS subjects (P<0.05). Forward stepwise regression analysis revealed that bilirubin was associated with increased GSH:GSSG ratio and reduced thiol concentrations, which, in addition to reduced circulating LDL, probably decreased oxLDL concentrations within the cohort. In addition, a marked reduction in total cholesterol concentrations in hyperbilirubinemic Gunn rats is presented (Gunn 0.570.09 versus control 1.690.40 mmol/L; P<0.001), arguing for a novel role for bilirubin in modulating lipid status in vivo. These findings implicate the physiological importance of bilirubin in protecting from atherosclerosis by reducing thiol and subsequent lipoprotein oxidation, in addition to reducing circulating LDL concentrations. 2012 Elsevier Inc. All rights reserved.
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Prosser, Hamish C.G.; Ng, Martin K.C.; Bursill, C. A.PURPOSE OF REVIEW: HDL and their main apolipoprotein (apo) constituent apoA-I are antiatherogenic. This has been predominantly attributed to the ability of apoA-I/HDL to efflux cholesterol from macrophages within atherosclerotic plaques. It is now emerging that a number of the protective properties of HDL may be due to their effects on the endothelium. RECENT FINDINGS: In addition to their well characterized anti-inflammatory and antioxidant effects, apoA-I and HDL regulate several other key biological pathways known to preserve endothelial function and promote vascular repair. The ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, and the scavenger receptor B type 1 mediate multiple intracellular signaling pathways as well as the efflux of cholesterol and/or oxysterols in response to apoA-I/HDL. Although cholesterol efflux triggers a host of signaling events in endothelial cells, there is evidence that some of the beneficial actions of HDL may occur independently of efflux. SUMMARY: Current data suggest that in endothelial cells ABCA1 and ABCG1 mediate the activation of intracellular signaling pathways primarily through the efflux of cholesterol and oxysterols to apoA-I/HDL. Interaction between HDL and scavenger receptor B type 1 initiates the greatest number of known signaling pathways and there is evidence that some of these are activated independent of efflux. 2012 Wolters Kluwer Health | Lippincott Williams &Wilkins.
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Stadler, Nadina; Heeneman, Sylvia; V, S. Adrian; Stanley, Naomi R.; Giles, Gregory I.; Gang, Bevan P.; Croft, Kevin D.; Mori, Trevor A.; Vata, Vladim; Daemen, Mat Jap; Waltenberger, Johannes L.; Davies, Michael J.Aims: Transition metal ions have been implicated in atherosclerosis. The goal of this study was to investigate whether metal ion levels were higher in people with diabetes, in view of their increased risk of aggravated atherosclerosis. Methods and results: Absolute concentrations of iron, copper, zinc and calcium, and products of protein and lipid oxidation were quantified in atherosclerotic lesions from subjects with (T2DM, n=27), without Type 2 diabetes (nonDM, n=22), or hyperglycaemia (HG, n=17). Iron (P<0.05), zinc (P<0.01) and calcium (P=0.01) were lower in T2DM compared to nonDM subjects. Copper levels were comparable. A strong correlation (r=0.618; P<0.001) between EPR-detectable and total iron in nonDM patients was not seen in T2DM. X-ray fluorescence microscopy revealed " hot spots" of iron in both T2DM and nonDM. Calcium and zinc co-localised and levels correlated strongly. F<inf>2</inf>-isoprostanes (P<0.05) and di-Tyr/Tyr ratio (P<0.025), oxidative damage markers were decreased in T2DM compared to nonDM, or HG. Conclusion: Advanced atherosclerotic lesions from T2DM subjects unexpectedly contained lower levels of transition metal ions, and protein and lipid oxidation products, compared to nonDM and HG. These data do not support the hypothesis that elevated metal ion levels may be a major causative factor in the aggravated atherosclerosis observed in T2DM patients. 2012 Elsevier Ireland Ltd.
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Borthwick, Faye; Warnakula, Samantha; Mangat, Rabban; Uwiera, Richard Re; Russell, James C.; Kelly, Sandra E.; Lee, Candace Y.; Hryshko, Larry V.; Mamo, John C.; Rye, Kerry Anne; Lopaschuk, Gary D.; Proctor, Spencer D.Objective: Low plasma high-density lipoprotein cholesterol (HDL-C) concentration is associated with the metabolic syndrome (MetS) and increased prevalence of cardiovascular disease (CVD). Animal and human studies report infusion of apolipoprotein A-1 (apoA-1) can reduce endothelial dysfunction, and/or induce regression of atherosclerosis. However, the direct mechanisms underlying the vascular benefits of either apoA-1 or HDL-C remain unclear. In this study, we assessed the ability of reconstituted HDL (rHDL) to improve vascular complications of MetS, including left ventricular (LV)-hypertrophy, arterial cholesterol deposition and myocardial lesion development. Methods and results: Obese insulin resistant (IR) JCR:LA-cp rats were infused with rHDL (0.4. mg/kg) over 3 days before assessing cardiac function (Echocardiography) at days 7 and 50 post-infusion, as well as haematoxylin and eosin staining of myocardial lesions at day 50. Acute ex vivo arterial cholesterol deposition was assessed with acute infusion of rHDL ex-vivo. Infusion of rHDL partially corrected abnormal diastolic compliance (18%; * p< 0.05) and improved parameters of cardiac function in IR rats. Further, acute rHDL infusion in carotid vessels reduced remnant lipoprotein associated-cholesterol deposition (30-86%; ** p< 0.01) ex vivo in IR and male Wistar rats and reduced (41%; * p< 0.05) the frequency of early-stage myocardial lesions in IR rats. Conclusion: Short-term infusion of rHDL may beneficially reduce chronic vascular sequelae of MetS, including temporary improvement in LV-dysfunction, acute reduction of acute arterial cholesterol deposition and the development of early-stage myocardial lesions in the JCR:LA-cp rat. 2012 Elsevier Ireland Ltd.
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Almine, Jessica F.; Wise, Steven G.; Weiss, Anthony StevenSkin is an important organ to the human body as it functions as an interface between the body and environment. Cutaneous injury elicits a complex wound healing process, which is an orchestration of cells, matrix components, and signaling factors that re-establishes the barrier function of skin. In adults, an unavoidable consequence of wound healing is scar formation. However, in early fetal development, wound healing is scarless. This phenomenon is characterized by an attenuated inflammatory response, differential expression of signaling factors, and regeneration of normal skin architecture. Elastin endows a range of mechanical and cell interactive properties to skin. In adult wound healing, elastin is severely lacking and only a disorganized elastic fiber network is present after scar formation. The inherent properties of elastin make it a desirable inclusion to adult wound healing. Elastin imparts recoil and resistance and induces a range of cell activities, including cell migration and proliferation, matrix synthesis, and protease production. The effects of elastin align with the hallmarks of fetal scarless wound healing. Elastin synthesis is substantial in late stage in utero and drops to a trickle in adults. The physical and cell signaling advantages of elastin in a wound healing context creates a parallel with the innate features of fetal skin that can allow for scarless healing. 2012 Wiley Periodicals, Inc.
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Truscott, Roger John Willis; Mizdrak, Jasminka; Friedrich, Michael G.; Hooi, Michelle Yu Sung; Lyons, Brian; Jamie, Joanne F.; Davies, Michael J.; Wilmarth, Phillip A.; David, Larry L.Since crystallins in the human lens do not turnover, they are susceptible to modification by reactive molecules over time. Methylation is a major post-translational lens modification, however the source of the methyl group is not known and the extent of modification across all crystallins has yet to be determined. Sites of methylation in human lens proteins were determined using HPLC/mass spectrometry following digestion with trypsin. The overall extent of protein methylation increased with age, and there was little difference in the extent of modification between soluble and insoluble crystallins. Several different cysteine and histidine residues in crystallins from adult lenses were found to be methylated with one cysteine (Cys 110 in ?D crystallin) at a level approaching 70%, however, methylation of crystallins was not detected in fetal or newborn lenses. S-adenosylmethionine (SAM) was quantified at significant (10-50 ?M) levels in lenses, and in model experiments SAM reacted readily with N-?-tBoc-cysteine and N-?-tBoc-histidine, as well as ?A3-crystallin. The pattern of lens protein methylation seen in the human lens was consistent with non-enzymatic alkylation. The in vitro data shows that SAM can act directly to methylate lens proteins and SAM was present in significant concentrations in human lens. Thus, non-enzymatic methylation of crystallins by SAM offers a possible explanation for this major human lens modification. 2012 Elsevier Ltd.
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Talib, Jihan; Pattison, David I.; Harmer, Jason A.; Celermajer, David S.; Davies, Michael J.Smokers have an elevated risk of atherosclerosis but the origin of this elevated risk is incompletely defined, though increasing evidence supports a role for the oxidant-generating enzyme myeloperoxidase (MPO). In previous studies we have demonstrated that smokers have elevated levels of thiocyanate ions (SCN -), relative to nonsmokers, and increased thiol oxidation, as SCN - is a favored substrate for MPO, and the resulting hypothiocyanous acid (HOSCN) targets thiol groups rapidly and selectively. In this study we show that increased HOSCN formation by MPO diminishes damage to nonthiol targets on both model proteins and human plasma proteins. Thus high SCN - levels protect against HOCl- and MPO-mediated damage to methionine, tryptophan, lysine, histidine, and tyrosine residues on proteins. Furthermore, levels of the HOCl-mediated marker compound 3-chlorotyrosine and the cross-linked product dityrosine are decreased. Plasma protein 3-chlorotyrosine levels induced by HOCl exposure in nonsmokers are elevated over the levels detected in smokers when exposed to identical oxidative insult (P<0.05), and a strong inverse correlation exists between plasma SCN - levels and 3-chlorotyrosine concentrations (r=0.6182; P<0.0001). These correlations were also significant for smokers (r=0.2724; P<0.05) and nonsmokers (r=0.4141; P<0.01) when analyzed as individual groups. These data indicate that plasma SCN - levels are a key determinant of the extent and type of protein oxidation induced by MPO on isolated and plasma proteins and that smoking status and resulting high SCN - levels can markedly modulate the levels of the widely used biomarker compound 3-chlorotyrosine. 2012 Elsevier Inc.
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McGrath, Kristine C.Y.; Heather, Alison Kay[No abstract available]
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Moheimani, Fatemeh; Kim, Christine H.J.; Rahmanto, Aldwin Suryo; Van Reyk, David M.; Davies, Michael J.Objective: People with diabetes have an elevated risk of atherosclerosis. The accumulation of lipid within macrophage cells in the artery wall is believed to arise via the uptake and subsequent processing of modified low-density lipoproteins (LDL) via the endo-lysosomal system. In this study the effects of prolonged exposure to elevated glucose upon macrophage lysosomal function was examined to determine whether this contributes to modulated protein catabolism. Methods: Human monocytes were isolated from white-cell concentrates and differentiated, in vitro, into monocyte-derived macrophages over 11 days in medium containing 5-30 mmol/L glucose. Murine macrophage-like J774A.1 cells were incubated similarly. Lysosomal cathepsin (B, D, L and S) and acid lipase activities were assessed using fluorogenic substrates; cathepsin protein levels were examined by Western blotting. Lysosomal numbers were examined using the lysomotropic fluorescent dye LysoTracker DND-99, measurement of aryl sulfatase activity, and quantification of lysosome-associated membrane glycoprotein-1 (LAMP-1) by Western blotting. Results: Exposure to elevated glucose, but not mannitol, resulted in a concentration-dependent decrease in the activity, and to a lesser extent protein levels, of four lysosomal cathepsins. Acid lipase activity was also significantly reduced. Arysulfatase activity, LAMP-1 levels and lysosomal numbers were also decreased at the highest glucose concentrations, though to a lesser extent. Conclusion: Long term exposure of human and murine macrophage cells to elevated glucose levels result in a depression of lysosomal proteolytic and lipase activities. This may result in decreased clearance and cellular accumulation of (lipo)proteins and contribute to the accumulation of modified proteins and lipids in diabetes-associated atherosclerosis. 2012 Elsevier Ireland Ltd.
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Li, Chao; Samaranayake, N. R.; Ong, Kwok Leung; Wong, Hoi Kin; Cheung, Bernard Man YungPurpose: Recent studies have implicated the human cytomegalovirus (HCMV) as a possible pathogen for causing hypertension. We aimed to study the association between HCMV infection and hypertension in the United States National Health and Nutrition Examination Survey (NHANES). Methods: We analyzed data on 2979 men and 3324 women in the NHANES 1999-2002. We included participants aged 16-49 years who had valid data on HCMV infection and hypertension. Results: Of the participants, 54.7% had serologic evidence of HCMV infection and 17.5% had hypertension. There were ethnic differences in the prevalence of HCMV infection (P<0.001) and hypertension (P<0.001). The prevalence of both increased with age (P<0.001). Before adjustment, HCMV seropositivity was significantly associated with hypertension in women (OR = 1.63, 95% CI = 1.25-2.13, P = 0.001) but not in men. After adjustment for race/ethnicity, the association between HCMV seropositivity and hypertension in women remained significant (OR = 1.55, 95% CI = 1.20-2.02, P = 0.002). Further adjustment for body mass index, diabetes status and hypercholesterolemia attenuated the association (OR = 1.44, 95% CI = 1.10-1.90, P = 0.010). However, after adjusting for age, the association was no longer significant (OR = 1.24, 95% CI = 0.91-1.67, P = 0.162). Conclusions: In this nationally representative population-based survey, HCMV seropositivity is associated with hypertension in women in the NHANES population. This association is largely explained by the association of hypertension with age and the increase in past exposure to HCMV with age. 2012 Li et al.
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Pattison, David I.; Davies, Michael J.; Hawkins, Clare L.Myeloperoxidase (MPO) is recognised to play important roles both in the immune system and during the development of numerous human pathologies. MPO is released by activated neutrophils, monocytes and some tissue macrophages, where it catalyses the conversion of hydrogen peroxide to hypohalous acids (HOX; X = Cl, Br, SCN) in the presence of halide and pseudo-halide ions. The major reactive species produced by MPO under physiological conditions are hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN), with the ratio of these oxidants critically dependent on the concentration of thiocyanate ions (SCN-). The reactivity and selectivity of HOCl and HOSCN for biological targets are markedly different, indicating that SCN- ions have the potential to modulate both the extent and nature of oxidative damage in vivo. This article reviews recent developments in our understanding of the role of SCN- in modulating the formation of MPO-derived oxidants, particularly in respect to the differences in reaction kinetics and targets of HOCl compared to HOSCN and the ability of these two oxidants to induce damage in biological systems. 2012 Informa UK, Ltd.
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Summers, Fiona A.; Forsman Quigley, Anna; Hawkins, Clare L.Hypochlorous acid (HOCl) is a potent oxidant produced by the enzyme myeloperoxidase, which is released by neutrophils under inflammatory conditions. Although important in the immune system, HOCl can also damage host tissue, which contributes to the development of disease. HOCl reacts readily with free amino groups to form N-chloramines, which also cause damage in vivo, owing to the extracellular release of myeloperoxidase and production of HOCl. HOCl and N-chloramines react readily with cellular thiols, which causes dysfunction via enzyme inactivation and modulation of redox signaling processes. In this study, the ability of HOCl and model N-chloramines produced on histamine and ammonia at inflammatory sites, to oxidize specific thiol-containing proteins in human coronary artery endothelial cells was investigated. Using a proteomics approach with the thiol-specific probe, 5-iodoacetamidofluorescein, we show that several proteins including peptidylprolyl isomerase A (cyclophilin A), protein disulfide isomerase, glyceraldehyde-3-phosphate dehydrogenase and galectin-1 are particularly sensitive to oxidation by HOCl and N-chloramines formed at inflammatory sites. This will contribute to cellular dysfunction and may play a role in inflammatory disease pathogenesis. 2012 Elsevier Inc.
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Barter, Philip J.; Rye, Kerry AnneHuman and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of torcetrapib. Copyright 2012 by the American Society for Biochemistry and Molecular Biology, Inc.
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Karlson, Bjn Wilgot; Barter, Philip J.; Palmer, Mike K.; Lundman, Pia; Nicholls, Stephen J.Background and aims: Diabetes mellitus is a well-known risk factor for cardiovascular disease, and brings an increased risk of vascular events and a higher mortality rate. Treatment guidelines recommend statins in patients with diabetes, with low-density lipoprotein cholesterol (LDL-C) targets of 100 mg dl-1 (?2.5 mmol l-1), and 80 (?2.0 mmol l-1) or 70 mg dl-1 (?1.8 mmol l-1) in especially high-risk patients. The current study used the VOYAGER (an indiVidual patient data-meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin, and simvastatin) database to characterise effects of rosuvastatin, atorvastatin and simvastatin in different doses on lipid levels in diabetes patients. Methods and results: The VOYAGER database included individual patient data from 37 studies involving comparisons of rosuvastatin with either atorvastatin or simvastatin. Of the 32 258 patients included, 8859 (27.5%) had diabetes. Rosuvastatin appeared to be the most efficacious of the three statins, both for lowering LDL-C and for reaching a target level of <70 mg dl-1 for LDL-C. It was also more effective than atorvastatin at raising high-density lipoprotein cholesterol in the diabetes population. These results are consistent with the overall VOYAGER results. Conclusions: This meta-analysis of 8859 patients with diabetes mellitus shows favourable effects on lipids with the three statins studied, in line with results for the overall VOYAGER population. The importance of using an effective statin at an effective dose to reach treatment goals for such high-risk patients is evident. 2012 Elsevier B.V.
