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Showing 1321–1340 of 2058 publications.
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Lambert, Gilles; Charlton, Francesca; Rye, Kerry Anne; Piper, Derek E.The LDL receptor (LDLr) inhibitor Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) has emerged as a genetically validated target for lowering plasma LDL cholesterol levels. In 2007, PCSK9 was found to act as a chaperone that binds the LDLr, thereby targeting it for lysosomal degradation. The enzymatic activity of PCSK9 is not involved in that process, but rather permits proper intramolecular processing of PCSK9. This was demonstrated by both site directed mutagenesis and independent reports of the PCSK9 crystal structure. These reports also elucidated the mode of action of several naturally occurring mutants of PCSK9 associated with hyper- or hypocholesterolemia. The present review summarizes studies published or in print before May 2008 investigating the functional significance of PCSK9 and its promising aspects as a prognostic tool and a drug target. 2008 Elsevier Ireland Ltd. All rights reserved.
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Reconstituted high-density lipoprotein attenuates postinfarction left ventricular remodeling in ratsKiya, Yoshihiro; Miura, Shinichiro; Imaizumi, Satoshi; Uehara, Yoshinari; Matsuo, Yoshino; Abe, Satomi; Jimi, Shiroh; Urata, Hidenori; Rye, Kerry Anne; Saku, KeijiroSince little is known about the effects of reconstituted high-density lipoprotein (rHDL) in left ventricular (LV) remodeling, these effects were examined in rats after acute myocardial infraction (MI). Sixteen male Wistar rats were randomly divided into three groups: Sham-operated (n = 6), and MI rats that received a permanent ligation around the proximal left coronary artery and infusions of placebo (MI group, n = 5) or rHDL (containing as apolipoproteinA-I 6 mg/kg) administered intravenously (MI + rHDL group, n = 5). rHDL was infused once a week for 4 weeks. In addition, in vitro assays were performed to examine the effect of rHDL. The MI + rHDL group showed a significant increase in LV ejection fraction (EF) between weeks 1 and 4, a decrease in LV end-systolic diameter, compared with the progressive deterioration of LV size and function in the MI group. In addition, the MI + rHDL group showed a significant decrease in fibrotic area of MI in LV compared to that in the MI group, while there were no significant increases in capillary density or cell size in LV in the MI + rHDL group. Interestingly, the MI + rHDL group showed a significant activation of retinoblastoma and ERK (extracellular-signal-regulated kinase) but not cleaved caspase-3, p38 MAPK or Jun N-terminal kinase. rHDL suppressed H<inf>2</inf>O<inf>2</inf>-induced arrest of cell growth in myocytes. This effect was blocked by PD98059, an ERK inhibitor. In conclusions, rHDL-promoted cell survival has beneficial morphological effects that help to prevent LV remodeling and improve function after MI, and may prevent arrest of cell growth through ERK pathway in myocytes. 2008 Elsevier Ireland Ltd. All rights reserved.
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Morgan, Philip E.; Sturgess, Allan D.; Davies, Michael J.Serum protein oxidation levels in people with the autoimmune disease systemic lupus erythematosus (SLE) have previously been shown to (a) be elevated at a single time point and (b) correlate with disease activity. This study investigates whether this elevation is a chronic phenomenon, by analysis of multiple serum samples collected from 21 SLE patients and nine controls over a period of up to 38 months. Protein thiols were chronically decreased in SLE patients with stable or variable disease activity compared to controls, whilst protein-bound carbonyls and glycine were chronically increased. 2D-gel analysis of carbonyl distribution showed albumin and immunoglobulins to be particularly affected. In SLE patients with stable disease activity, higher long-term protein oxidation correlated with higher long-term disease activity. SLE patients with variable disease activity exhibited varying correlations between protein oxidation and disease activity markers. These results further support a role for oxidative stress in the pathogenesis of SLE.
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Chapman, Anna L.P.; Skaff, Ojia; Senthilmohan, Revathy; Kettle, Anthony James; Davies, Michael J.MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate to their respective hypohalous acids.We have investigated the generation of HOBr by human neutrophils in the presence of physiological concentrations of chloride and bromide. HOBrwas trappedwith taurine and detected by monitoring the bromination of 4-HPAA (4-hydroxyphenylacetic acid). With 100 ?M bromide and 140 mM chloride, neutrophils generated HOBr and it accounted for approx. 13% of the hypohalous acids they produced. Addition of SOD (superoxide dismutase) doubled the amount of HOBr detected. Therefore we investigated the reaction of superoxide radicals with a range of bromamines and bromamides and found that superoxide radicals stimulated the decomposition of these species, with this occurring in a time- and dose-dependent manner. The protection afforded by SOD against such decay demonstrates that these processes are superoxideradical-dependent. These data are consistent with neutrophils generating HOBr at sites of infection and inflammation. Both HOBr and bromamines/bromamides have the potential to react with superoxide radicals to form additional radicals that may contribute to inflammatory tissue damage. The Authors Journal compilation 2009 Biochemical Society.
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McRobb, Lucinda S.; Handelsman, David J.; Heather, Alison KayArterial calcification has prognostic significance for cardiovascular outcomes, but its pathogenesis remains unclear. Calcification increases with age, but its prevalence in men suggests hormonal influence. In this study we analyzed the effect of exogenous androgens on calcification of advanced atherosclerotic lesions in the arterial tree of gonadally intact 34-wk-old male and female apolipoprotein E-null mice. Testosterone (T) increased calcification 3-to 4-fold (P < 0.05) in lesions of the innominate artery and aortic sinus. A nonaromatizable androgen, dihydrotestosterone, also increased lesion calcification in the innominate artery (2.4-fold, P < 0.05) but not the aortic sinus. The androgen-induced effects were independent of sex and occurred despite corresponding reductions in plaque area, the latter correlating inversely with increased serum high-density lipoprotein cholesterol levels. Androgen-induced calcification in the innominate artery was observed with up-regulation of local androgen receptor (AR) expression in response to T and dihydrotestosterone for both males and females but neither androgen influenced innominate artery estrogen receptor (ER)-? or ? expression in either sex. Conversely, T-induced calcification in the aortic sinus was associated with down-regulation of ER? but not ER? expression in both sexes, whereas androgen- induced AR expression was increased in female but decreased in male mice. This study demonstrates for the first time that calcification of advanced atherosclerotic lesions is an androgen - sensitive process and postulates potential roles for both AR- and ER-mediated pathways in androgen-induced vascular calcification. We demonstrate a novel direct link between vascular calcification and the major male hormone, T, uncoupled from conventional relationships with plaque growth and lipid levels. Copyright 2009 by The Endocrine Society.
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Schwartz, Gregory G.; Olsson, Anders G.; Ballantyne, Christie Mitchell; Barter, Philip J.; Holme, Ingar Morten K.; Kallend, David G.; Leiter, Lawrence Alan; Leitersdorf, Eran; McMurray, John JV; Shah, Prediman Krishan; Tardif, Jean Claude; Chaitman, Bernard R.; Duttlinger-Maddux, Regina; Mathieson, JohnBackground: Despite contemporary therapies for acute coronary syndrome (ACS), morbidity and mortality remain high. Low levels of high-density lipoprotein (HDL) cholesterol are common among patients with ACS and may contribute to ongoing risk. Strategies that raise levels of HDL cholesterol, such as inhibition of cholesterol ester transfer protein (CETP), might reduce risk after ACS. Dal-OUTCOMES is a multicenter, randomized, double-blind, placebo-controlled trial designed to test the hypothesis that CETP inhibition with dalcetrapib reduces cardiovascular morbidity and mortality in patients with recent ACS. Design: The study will randomize approximately 15,600 patients to receive daily doses of dalcetrapib 600 mg or matching placebo, beginning 4 to 12 weeks after an index ACS event. There are no prespecified boundaries for HDL cholesterol levels at entry. Other elements of care, including management of low-density lipoprotein cholesterol, are to follow best evidence-based practice. The primary efficacy measure is time to first occurrence of coronary heart disease death, nonfatal acute myocardial infarction, unstable angina requiring hospital admission, resuscitated cardiac arrest, or atherothrombotic stroke. The trial will continue until 1,600 primary end point events have occurred, all evaluable subjects have been followed for at least 2 years, and 80% of evaluable subjects have been followed for at least 2.5 years. Summary: Dal-OUTCOMES will determine whether CETP inhibition with dalcetrapib, added to current evidence-based care, reduces cardiovascular morbidity and mortality after ACS.
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Cannon, Christopher Paul; Dansky, Hayes M.; Davidson, Michael H.; Gotto, Antonio M.; Brinton, Eliot A.; Gould, A. Lawrence; Stepanavage, Michael E.; Liu, Sherry Xueyu; Shah, Sukrut; Rubino, Joseph; Gibbons, Patrice H.; Hermanowski-Vosatka, Anne; Binkowitz, Bruce S.; Mitchel, Yale B.; Barter, Philip J.Background: Residual cardiovascular (CV) risk often remains high despite statin therapy to lower low-density lipoprotein cholesterol (LDL-C). New therapies to raise high-density lipoprotein cholesterol (HDL-C) are currently being investigated. Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that raises HDL-C and reduces LDL-C when administered alone or with a statin. Adverse effects on blood pressure, electrolytes, and aldosterone levels, seen with another drug in this class, have not been noted in studies of anacetrapib to date. Methods: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE) is a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease (CHD) or CHD risk equivalents (clinical trials.gov NCT00685776). Eligible patients at National Cholesterol Education Program-Adult Treatment Panel III LDL-C treatment goal on a statin, with or without other lipid-modifying medications, are treated with anacetrapib, 100 mg, or placebo for 18 months, followed by a 3-month, poststudy follow-up. The primary end points are percent change from baseline in LDL-C and the safety and tolerability of anacetrapib. Comprehensive preplanned interim safety analyses will be performed at the 6- and 12-month time points to examine treatment effects on key safety end points, including blood pressure and electrolytes. A preplanned Bayesian analysis will be performed to interpret the CV event distribution, given the limited number of events expected in this study. Results: A total of 2,757 patients were screened at 153 centers in 20 countries, and 1,623 patients were randomized into the trial. Lipid results, clinical CV events, and safety outcomes from this trial are anticipated in 2010. 2009 Mosby, Inc. All rights reserved.
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Chirovsky, Diana Romana; Fedirko, Veronika; Cui, Yadong; Sazonov-Kocevar, Vasilisa; Barter, Philip J.Epidemiological studies have extensively evaluated the association between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) risk. The objective of this systematic review was to enumerate the number of original prospective studies that showed a significant association between HDL-C and CVD risk and provided evidence of the consistency of this association across other lipid risk factors. A systematic MEDLINE literature search identified 53 prospective cohort and five nested case-control studies that provided multivariate assessments of the association between HDL-C and CVD risk. Among these 58 prospective studies, 31 studies found a significant inverse association between HDL-C and CVD risk for all CVD outcomes and subpopulations studied, whereas 17 studies found a significant association for some CVD outcomes and/or subpopulations assessed. The ratio of studies that found a significant association out of the total studies identified was similar across all CVD outcomes, although there was less evidence for stroke and atherosclerotic outcomes. Only seven studies tested for the consistency of this association across other lipid risk factors, of which six studies suggested that the association was consistent across other lipid levels. In conclusion, the association between HDL-C and CVD risk is significant and strong, although further evidence may be needed to establish whether this association is consistent across other lipid risk factors. Furthermore, uncertainties remain regarding the mechanism in which HDL-C exerts its effects, suggesting a need for further research focused on new methods for reliable measurement. 2009 The European Society of Cardiology.
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Tabet, Fatiha; Rye, Kerry AnnePlasma levels-of HDL (high-density lipoprotein)-cholesterol are strongly and inversely correlated with atherosclerotic cardiovascular disease. Both clinical and epidemiological studies have reported an inverse and independent association between serum HDL-cholesterol levels and CHD (coronary heart disease) risk. The cardioprotective effects of HDLs have been attributed to several mechanisms, including their involvement in the reverse cholesterol transport pathway. HDLs also have antioxidant, anti-inflammatory and antithrombotic properties and promote endothelial repair, all of which are likely to contribute to their ability to prevent CHD. The first part of this review summarizes what is known about the origins and metabolism of HDL. We then focus on the anti-inflammatory and antioxidant properties of HDL and discuss why these characteristics are cardioprotective. The Authors Journal compilation 2009 Biochemical Society.
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Carmel, Jean Franis; Tarnus, Evelyne; Cohn, Jeffrey S.; Bourdon, Emmanuel; Davignon, Jean; Bernier, LiseApolipoprotein E (apoE), a key regulator of lipid metabolism, is highly produced by adipose tissue and adipocytes. However, there is little information about its role on adipocyte functions. Because apoE-deficiency in adipocytes was shown to impair adipocyte differentiation, we investigated the consequences of apoE high expression on differentiation and proliferation of a human adipocytic cell line (SW872). SW872 cells were transfected with human apoE to induce a fivefold increase in apoE production and secretion. Adipocyte differentiation and proliferation were assayed by measuring lipid content, adipogenic gene expression, cell number, cell resistance to serum deprivation, and cell division kinetics. Cultured apoE-transfected cells accumulated less triglycerides and less cholesterol than control cells. This decrease in lipid accumulation was associated with a strong downregulation of peroxisome proliferator-activated receptors ?1 and ?2 and stearoyl-CoA desaturase 1. The decrease in lipid accumulation was not dependent on the presence of lipids, lipoproteins, or PPAR-? agonists in the culture medium, nor was it observed with exogenously added apoE. Moreover, we observed that apoE-transfected cells were more resistant to death induced by serum deprivation, and that these cells underwent more cell divisions than control cells. These results bring new evidence of apoE-involvement in metabolic disorders at the adipocyte level. 2009 Wiley-Liss, Inc.
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Maternal parity affects neonatal survival rate in a colony of captive bred baboons (Papio hamadryas)Sunderland, Neroli; Heffernan, Scott J.; Thomson, Sally E.; Hennessy, AnnemarieBackground: Non-human primates, particularly baboons, are valuable as animal models for reproductive research, because of their similarity to humans. Knowledge of colony-specific pregnancy and neonatal outcomes is essential for interpretation of such research. Methods: A retrospective review of the reproductive records of the Australian National Baboon Colony (ANBC) from 1994 to 2006 was performed. Results: The overall live birth rate was over 70% of recognized pregnancies. Pregnancy loss was due to equal proportions of spontaneous abortion and stillbirth, and was not affected by maternal age or parity. Stillbirth rates were increased by the use of animals in novel late pregnancy experimental protocols. Neonatal mortality rates were low overall, but significantly higher in primiparous compared with multiparous mothers (P < 0.05). There were no cases of maternal mortality. Conclusions: The success of the ANBC breeding programme is demonstrated by the low rate of pregnancy loss, high neonatal survival rate and lack of maternal mortality. 2008 The Author Journal compilation 2008 Blackwell Munksgaard.
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Barter, Philip J.; Ginsberg, Henry N.Combination therapy for the treatment of dyslipidemia and reduction of cardiovascular risk has been demonstrated to beneficially modify the lipid profile in multiple randomized clinical trials. As reported in the updated National Cholesterol Education Program Adult Treatment Panel III guidelines, low-density lipoprotein (LDL) cholesterol remains the primary treatment target, although the comprehensive management of dyslipidemia in high-risk patients includes the modification of secondary lipid parameters such as triglycerides, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol. Although statin therapy is the standard intervention for lowering LDL cholesterol, combination therapy has demonstrated added benefits on secondary lipid parameters and enhances statin-mediated reductions in LDL cholesterol. The benefits of modifying these secondary targets on all-cause or cardiovascular event-related mortality are currently under investigation in several clinical trials. Prescription omega-3 fatty acid (Lovaza) is a formulation of 2 highly purified omega-3-acid ethyl esters, eicosapentaenoic acid and docosahexaenoic acid. The recently completed Combination of Prescription Omega-3 With Simvastatin (COMBOS) study confirmed that prescription omega-3 fatty acid administered in combination with simvastatin achieves statistically significant improvements across a range of lipid indicators beyond the LDL primary target, including triglycerides, non-high-density lipoprotein cholesterol, and lipoprotein particle size. In conclusion, several classes of drugs, including omega-3 fatty acids, can be used in combination with statins to achieve more global improvements in lipid profiles. 2008 Elsevier Inc. All rights reserved.
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Patel, Sanjay[No abstract available]
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Barter, Philip J.; Rye, Kerry Anne[No abstract available]
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Siggins, Sarah L.; Rye, Kerry Anne; Olkkonen, Vesa M.; Jauhiainen, Matti Sakari; Ehnholm, Christian P.[No abstract available]
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Morgan, Philip E.; Pattison, David I.; Hawkins, Clare L.; Davies, Michael J.Hydroperoxides are major reaction products of radicals and singlet oxygen with amino acids, peptides, and proteins. However, there are few data on the distribution of hydroperoxides in biological samples and their sites of formation on peptides and proteins. In this study we show that normal-or reversed-phase gradient HPLC can be employed to separate hydroperoxides present in complex systems, with detection by postcolumn oxidation of ferrous xylenol orange to the ferric species and optical detection at 560 nm. The limit of detection (10-25 pmol) is comparable to chemiluminescence detection. This method has been used to separate and detect hydroperoxides, generated by hydroxyl radicals and singlet oxygen, on amino acids, peptides, proteins, plasma, and intact and lysed cells. In conjunction with EPR spin trapping and LC/MS/MS, we have obtained data on the sites of hydroperoxide formation. A unique fingerprint of hydroperoxides formed at ?-carbon (backbone) positions has been identified; such backbone hydroperoxides are formed in significant yields only when the amino acid is part of a peptide or protein. Only side-chain hydroperoxides are detected with free amino acids. These data indicate that free amino acids are poor models of protein damage induced by radicals or other oxidants. 2008 Elsevier Inc. All rights reserved.
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Rye, Kerry Anne; Barter, Philip J.[No abstract available]
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Machaalani, Rita; Makris, Angela; Thornton, Charlene Eliza; Hennessy, AnnemarieObjective: To test the hypothesis that vascular endothelial growth factor receptor 1 (Flt1) is negatively correlated with apoptosis in preeclampsia placentae, and to examine the effects of antihypertensive medication on apoptosis. Methods: Flt1 and TUNEL immunoreactivity were quantitatively compared in the stromal decidual cells, villous trophoblasts, and endothelial cells of placentae from uncomplicated pregnancies (NP, n = 34) to those in patients with preeclampsia (PE, n = 30), and those in patients with preeclampsia with superimposed intrauterine growth restriction (PE + IUGR, n = 7). Further analyses determined any correlations with the antepartum use of the antihypertensives clonidine and hydralazine. Results: There was no difference in either Flt1 or TUNEL when comparing PE placentae (with or without IUGR) with NP. There were no correlations with the use of the antihypertensives. Conclusion. Apoptotic levels do not correlate with Flt1 in preeclampsia placentae and are not regulated by invivo exposure to the antihypertensives clonidine and hydralazine. Copyright Informa Healthcare USA, Inc.
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Lam, Magdalena A.; Pattison, David I.; Bottle, Steven E.; Keddie, Daniel J.; Davies, Michael J.Nitric oxide (NO) may act as either a pro-oxidant or an antioxidant in biological systems. Although NO and nitroxide radicals react slowly with most molecules, they react at near diffusion-controlled rates with other radicals and may therefore be efficient protective agents. This study assessed the ability of NO and nitroxides to intercept specific protein-derived radicals and compared the efficacy of these species. Three protein radical systems were investigated as follows: BSA-derived radicals generated via radical transfer from H <inf>2</inf>O<inf>2</inf>-activated horseradish peroxidase, radicals formed on myoglobin via reaction with H<inf>2</inf>O<inf>2</inf>, and carbon-centered radicals formed from amino acid hydroperoxides on exposure to Fe 2+-EDTA. In each case, radicals were generated in the absence or presence of NO or nitroxides of different size and charge. Concentration-dependent loss of the protein radicals was detected by electron paramagnetic resonance with both NO and nitroxides and time-dependent consumption of NO using an NO electrode. The protein oxidation product dityrosine was significantly reduced by NO and nitroxides, and 3,4-dihydroxyphenylalanine levels were reduced by nitroxides but not NO. Overall, these studies demonstrate that NO and nitroxides are efficient near-stoichiometric scavengers of protein radicals and, hence, are potential protective agents against protein oxidation reactions and resulting damage. These reactions show little dependence on nitroxide structure or charge. 2008 American Chemical Society.
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Hawkins, Clare L.; Pattison, David I.; Stanley, Naomi R.; Davies, Michael J.Myeloperoxidase, released by activated phagocytes, forms reactive oxidants by catalysing the reaction of halide and pseudo-halide ions with H<inf>2</inf>O<inf>2</inf>. These oxidants have been linked to tissue damage in a range of inflammatory diseases. With physiological levels of halide and pseudo-halide ions, similar amounts of HOC1 (hypochlorous acid) and HOSCN (hypothiocyanous acid) are produced by myeloperoxidase. Although the importance of HOSCN in initiating cellular damage via thiol oxidation is becoming increasingly recognized, there are limited data on the reactions of HOSCN with other targets. In the present study, the products of the reaction of HOSCN with proteins has been studied. With albumin, thiols are oxidized preferentially forming unstable sulfenyl thiocyanate derivatives, as evidenced by the reversible incorporation of 14C from HOS 14CN. On consumption of the HSA (human serum albumin) free thiol group, the formation of stable 14C-containing products and oxidation of tryptophan residues are observed. Oxidation of tryptophan residues is observed on reaction of HOSCN with other proteins (including myoglobin, lysozyme and trypsin inhibitor), but not free tryptophan, or tryptophan-containing peptides. Peptide mass mapping studies with HOSCN-treated myoglobin, showed the addition of two oxygen atoms on either Trp7 or Trp14 with equimolar or less oxidant, and the addition of a further two oxygen atoms to the other tryptophan with higher oxidant concentrations (? 2-fold). Tryptophan oxidation was observed on treating myoglobin with HOSCN in the presence of glutathione and ascorbate. Thus tryptophan residues are likely to be favourable targets for the reaction in biological systems, and the oxidation products formed may be useful biomarkers of HOSCN-mediated protein oxidation. The Authors Journal compilation.
