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Showing 1281–1300 of 2058 publications.
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Rees, Martin D.; Whitelock, John; Malle, Ernst; Chuang, Christine Y.; Iozzo, Renato V.; Nilasaroya, Anastasia; Davies, Michael J.The potent oxidants hypochlorous acid (HOCl) and hypobromous acid (HOBr) are produced extracellularly by myeloperoxidase, following release of this enzyme from activated leukocytes. The subendothelial extracellular matrix is a key site for deposition of myeloperoxidase and damage by myeloperoxidase-derived oxidants, with this damage implicated in the impairment of vascular cell function during acute inflammatory responses and chronic inflammatory diseases such as atherosclerosis. The heparan sulfate proteoglycan perlecan, a key component of the subendothelial extracellular matrix, regulates important cellular processes and is a potential target for HOCl and HOBr. It is shown here that perlecan binds myeloperoxidase via its heparan sulfate side chains and that this enhances oxidative damage by myeloperoxidase-derived HOCl and HOBr. This damage involved selective degradation of the perlecan protein core without detectable alteration of its heparan sulfate side chains, despite the presence of reactive GlcNH<inf>2</inf> residing within this glycosaminoglycan. Modification of the protein core by HOCl and HOBr (measured by loss of immunological recognition of native protein epitopes and the appearance of oxidatively-modified protein epitopes) was associated with an impairment of its ability to support endothelial cell adhesion, with this observed at a pathologically-achievable oxidant dose of 425 nmol oxidant/mg protein. In contrast, the heparan sulfate chains of HOCl/HOBr-modified perlecan retained their ability to bind FGF-2 and collagen V and were able to promote FGF-2-dependent cellular proliferation. Collectively, these data highlight the potential role of perlecan oxidation, and consequent deregulation of cell function, in vascular injuries by myeloperoxidase-derived HOCl and HOBr. 2009 Elsevier B.V. All rights reserved.
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Nicholls, Stephen J.; Brandrup-Wognsen, Gunnar; Palmer, Mike K.; Barter, Philip J.Statins are the most commonly prescribed agents for lowering levels of low-density lipoprotein (LDL) cholesterol. Although dose-dependent reductions in levels of atherogenic lipids are observed with all statins, the impact of increasing dose has not been fully elucidated. An individual patient data pooled analysis was performed of 32,258 patients in studies comparing the efficacy of rosuvastatin with that of atorvastatin or simvastatin. The impact of increasing dose on lowering LDL cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B was investigated. Doubling the dose of each statin was accompanied by a 4% to 7% greater degree of lowering of all atherogenic lipids. A stronger correlation was observed between changes in LDL cholesterol and non-HDL cholesterol (r = 0.92, p <0.001) or apolipoprotein B (r = 0.76, p <0.001) than triglycerides (r = 0.14, p <0.001). On multivariate analysis, baseline lipid level (p <0.0001) and increasing statin dose (p <0.0001) were strong predictors of achieving treatment goals in high-risk patients. Increasing age was a strong independent predictor of achieving goal for all atherogenic lipids (p <0.0001). Achieving LDL cholesterol goals was also more likely in women (p <0.0001), patients with diabetes (p <0.0001), and patients without atherosclerotic disease (p = 0.0002). In contrast, normal triglyceride levels were more often observed in men (p <0.0001) and patients without diabetes mellitus (p = 0.03). In conclusion, doubling statin dose was associated with greater lowering of LDL cholesterol by 4% to 6% and non-HDL cholesterol by 3% to 6%. Greater lipid goal achievement with increasing dose supports the use of high-dose statin therapy for more effective cardiovascular prevention. 2010 Elsevier Inc. All rights reserved.
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Szuchman-Sapir, Andrea J.; Pattison, David I.; Davies, Michael J.; Witting, Paul KennethMyeloperoxidase catalyzes the reaction of chloride ions with H<inf>2</inf>O<inf>2</inf> to yield hypochlorous acid (HOCl), which can damage proteins. Human myoglobin (HMb) differs from other Mbs by the presence of a cysteine residue at position 110 (Cys110). This study has (i) compared wild-type and a Cys110Ala variant of HMb to assess the influence of Cys110 on HOCl-induced amino acid modification and (ii) determined whether HOCl oxidation of HMb affects the rate of ferric heme reduction by cytochrome b<inf>5</inf>. For wild-type HMb (HOCl:Mb ratio of 5:1mol:mol), Cys110 was preferentially oxidized to a homodimeric or cysteic acid product-sulfenic/sulfinic acids were not detected. At a HOCl:Mb ratio 10:1mol:mol, methionine (Met) oxidation was detected, and this was enhanced in the Cys110Ala variant. Tryptophan (Trp) oxidation was detected only in the Cys110Ala variant at the highest HOCl dose tested, with oxidation susceptibility following the order Cys > Met > Trp. Tyrosine chlorination was evident only in reactions between HOCl and the Cys110Ala variant and at a longer incubation time (24h), consistent with the formation via chlorine-transfer reactions from preformed chloramines. HOCl-mediated oxidation of wild-type HMb resulted in a dose-dependent decrease in the observed rate constant for ferric heme reduction (approx two-fold at HOCl:Mb of 10:1mol:mol). These data indicate that Cys110 influences the oxidation of HMb by HOCl and that oxidation of Cys, Met, and Trp residues is associated with a decrease in the one-electron reduction of ferric HMb by other proteins; such heme-Fe3+ reduction is critical to the maintenance of function as an oxygen storage protein in tissues. Crown Copyright 2009.
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Skaff, Ojia; Pattison, David I.; Davies, Michael J.MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate by H<inf>2</inf>O<inf>2</inf> to HOCl (hypochlorous acid), HOBr (hypobromous acid) and HOSCN (hypothiocyanous acid, also know as cyanosulfenic acid) respectively. Specificity constants indicate that thiocyanate, SCN-, is a major substrate for MPO. HOSCN is also a major oxidant generated by other peroxidases including salivary, gastric and eosinophil peroxidases. Whereas HOCl and HOBr are powerful oxidizing agents, HOSCN appears to be a less reactive, but more thiol-specific oxidant. Although it is established that HOSCN selectively targets thiols, absolute kinetic data for the reactions of thiols with HOSCN are absent from the literature. This study shows for the first time that the reactions of HOSCN with low-molecular- mass thiol residues occur with rate constants in the range from 7.3 103 M-1 s-1 (for N-acetyl-cysteine at pH 7.4) to 7.7 106 M-1 s-1 (for 5-thio-2-nitrobenzoic acid at pH 6.0). An inverse relationship between the rate of reaction and the pK<inf>a</inf> of the thiol group was observed. The rates of reaction of HOSCN with thiol-containing proteins were also investigated for four proteins (creatine kinase, BSA, ?-lactoglobulin and ?-L-crystallins). The values obtained for cysteine residues on these proteins are in the range 1 104- 7 104 M-1 s-1. These second-order rate constants indicate that HOSCN is a major mediator of thiol oxidation in biological systems exposed to peroxidase/H<inf>2</inf>O<inf>2</inf> systems at (patho)physiological concentrations of halide and SCN- ions, and that HOSCN may play an important role in inflammation-induced oxidative damage. The Authors Journal compilation.
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Strychar, Irene M.; Cohn, Jeffrey S.; Renier, Genevie; Rivard, Miche; Aris-Jilwan, Nahla; Beauregard, Hugues F.; Meltzer, Sara J.; Banger, Andr Dumas, Richard; Ishac, Alain; Radwan, Farouk; Yale, Jean FranisOBJECTIVE - To compare the effects of a eucaloric diet higher in carbohydrate/lower in fat versus lower in carbohydrate/higher in monounsaturated fat on postmeal triglyceride (TG) concentrations and other cardiovascular disease risk factors in nonobese subjects with type 1 diabetes and in good glycemic control. RESEARCH DESIGN AND METHODS - In a parallel group design study, 30 subjects were randomly assigned and completed one of the two eucaloric diets. Assessments included: BMI, blood pressure, A1C, plasma lipids, and markers of oxidation, thrombosis, and inflammation. At 6 months, subjects were hospitalized for 24 h to measure plasma TG excursions. RESULTS - There were no significant differences between groups other than decreased plasminogen activator inhibitor 1 (PAI-1) levels and weight gain in the lower-carbohydrate/ higher-monounsaturated fat group. During the 24-h testing, the lower-carbohydrate/higher-monounsaturated fat group had a lower plasma TG profile. CONCLUSIONS - A diet lower in carbohydrate/higher in monounsaturated fat could offer an appropriate choice for nonobese type 1 diabetic individuals with good metabolic and weight control. 2009 by the American Diabetes Association.
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Meyer, Barbara J.; Lane, Amanda E.; Mann, Neil J.As meat is a rich source of the omega-3 fatty acid docosapentaenoic acid (DPA) and Australians consume six times more meat than fish, investigation of the potential health benefit of DPA is warranted. The aims were to compare the effects of seal oil supplementation with fish oil, on measures of plasma lipids and blood pressure in hypertriglyceridaemic subjects. Forty-eight volunteers were recruited from the Wollongong community and were randomly allocated to one of three groups either receiving 1 g/day of long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) using one of three oils: seal oil capsules (340 mg eicosapentaenoic acid (EPA), 230 mg DPA, 450 mg DHA), fish oil capsules (210 mg EPA, 30 mg DPA, 810 mg DHA) or placebo capsules (containing sunola oil) for 6 weeks. Plasma triglycerides remained unchanged in the placebo group, whilst reductions of 7 and 14% (P < 0.05) were seen in the fish oil and seal oil groups respectively. Systolic blood pressure improved by 8 and 5 mmHg with seal oil and fish oil respectively (P < 0.05). The mean arterial pressure was significantly lower after seal oil supplementation (P < 0.005) compared with the placebo group. These results indicate that seal oil is as effective as fish oil in lowering plasma triglycerides and blood pressure. 2009 AOCS.
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Thompson, Alisha M.; Dunlop, Rachael Anne; Dean, Roger T.; Rodgers, Kenneth JohnThe adhesive and cohesive properties of the amino acid L-3,4-dihydroxyphenylalanine (DOPA) have been widely explored as a potential material for adhesion, based, among other things, on the biological system of blue mussel extracellular byssal threads and foot proteins. Proteins containing DOPA are generated within mammalian cells by oxidation of tyrosine residues during periods of oxidative stress. By generating proteins containing DOPA, in vitro, through the (mis)incorporation of DOPA during protein synthesis, we are able examine the role and fate of DOPA-containing proteins in mammalian cells. We demonstrate a decrease in catabolism of long half-life cell proteins and an increase in cellular autofluorescence when DOPA is present in cell proteins. We provide evidence for the formation of DOPA derivatives which can be detected in proteins after 14C-DOPA incorporation by HPLC analysis. Additionally, we demonstrate that the cells upregulate the expression of genes required to handle damaged proteins and protein aggregates under these conditions. Substantial evidence for DOPA derivatives and cross-linking has previously been shown in extracellular blue mussel byssal threads; here we provide evidence for cell-associated DOPA derivatives in mammalian cells.
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Wu, Ben Jing; Midwinter, Robyn G.; Cassano, Juan Carlos; Beck, Konstanze; Wang, Yutang; Changsiri, Dechaboon; Gamble, Jennifer R.; Stocker, RolandOBJECTIVES-: Induction of heme oxygenase-1 (HO-1) protects against atherosclerotic disease in part by promoting reendothelialization. As endothelial progenitor cells (EPCs) contribute to reendothelialization, we examined the role of HO-1 on bone marrow and circulating EPCs. METHODS AND RESULTS-: In a rabbit model of aortic balloon injury, pharmacological induction of HO-1 enhanced reendothelialization at sites with and without adjacent blood vessels, the latter indicative of a contribution by EPCs. Coinciding with maximal HO-1 induction in the injured vessel, plasma concentrations of bilirubin and the numbers of circulating progenitor cells were elevated. Both processes were abolished by cotreatment of the animals with an inhibitor of HO-1. Inducers of HO-1 promoted bone marrow cells to form progenitor cell colonies, and Flk1/Sca-1-cells to adhere to the luminal surface of the injured vessel. In noninjured mice, HO-1 inducers also increased bone marrow and circulating EPCs, and the ability of these cells to differentiate and form colonies. Compared to wild-type mice, bone marrow cells from HO-1 mice generated fewer endothelial colony-forming cells, and HO-1 inducers failed to promote CFU-Hill colony formation. CONCLUSIONS-: These findings suggest that HO-1 contributes to vascular repair by increasing circulating EPCs derived from the bone marrow. 2009 American Heart Association, Inc.
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Tandy, Sally; Chung, Rosanna W.S.; Elaine, W. A.T.; Berge, Alvin Kamili Kjetil; Griinari, Mikko; Cohn, Jeffrey S.Krill oil (KO) is rich in n-3 fatty acids that are present in phospholipids rather than in triglycerides. In the present study, we investigated the effects of dietary KO on cardiometabolic risk factors in male C57BL/6 mice fed a high-fat diet. Mice (n = 6-10 per group) were fed for 8 weeks either: (1) a nonpurified chow diet (N); (2) a high-fat semipurified diet containing 21 wt % buttermilk + 0.15 wt % cholesterol (HF); (3) HF supplemented with 1.25 wt % KO (HFK01.25); (4) HF with 2.5 wt % KO (HFK02.5); or (5) HF with 5 wt % KO (HFKO5.0). Dietary KO supplementation caused a significant reduction in liver wt (i.e., hepatomegaly) and total liver fat (i.e., hepatic steatosis), due to a dosedependent reduction in hepatic triglyceride (mean SEM: 35 6, 47 4, and 51 5% for HFKO1.25, -2.5, and -5.0 vs HF, respectively, P < 0.001) and cholesterol (55 5, 66 3, and 71 3%, P < 0.001). Serum cholesterol levels were reduced by 20 3, 29 4, and 29 5%, and blood glucose was reduced by 36 5, 34 6, and 42 6%, respectively. Serum adiponectin was increased in KO-fed animals (HF vs HFKO5.0: 5.0 0.2 vs 7.5 0.6 ?g/mL, P < 0.01). These results demonstrate that dietary KO is effective in improving metabolic parameters in mice fed a high-fat diet, suggesting that KO may be of therapeutic value in patients with the metabolic syndrome and/or nonalcoholic fatty liver disease. 2009 American Chemical Society.
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Davies, Michael J.; Hanson, Graeme R.; Pilbrow, John R.[No abstract available]
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Grover, Steven A.; Kaouache, Mohammed; Joseph, Lawrence; Barter, Philip J.; Davignon, JeanBackground: The role of high-density lipoprotein cholesterol (HDL-C) as a therapeutic target to prevent cardiovascular (CV) events remains unclear. We examined data from the Framingham Offspring Study from 1975 through 2003 to determine whether increases in HDL-C levels after lipid therapy was started were independently associated with a reduction in CV events. Methods: UsingCoxproportional-hazards regression,we evaluated the risk of a CV event associated with changes in blood lipid levels among individuals who started lipid therapy. The independent effect ofHDL-Clevels on future CVrisk (average follow-up,8years)wasestimated after adjustment forchangesin low-density lipoprotein cholesterol, plasma triglycerides, and pretreatment blood lipid levels. Potential confounders (eg, smoking status, weight, and the use of ?-blockers) were then added to the model. Interactions between blood lipid levels were also explored. Results: Thechange inHDL-Clevel was a strong independent risk factor forCVevents (hazard ratio, 0.79 per 5-mg/ dL increase; 95% confidence interval, 0.67-0.93) after adjustment for the other lipid changes associated with treatment. This relationship remained stable across a wide range of patientsubgroupsanddidnotappeartobeassociatedwith a specificdrugclass.Animportant interactionwasobserved: the lower the pretreatment low-density lipoprotein cholesterol level, the greater the impact of raising the HDL-C. Conclusions: Raising HDL-C levels with commonly used lipid medications appears to be an important determinant of the benefits associated with lipid therapy. These results support the further evaluation of therapies to raise HDL-C levels to prevent CV events. 2009 American Medical Association. All rights reserved.
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Xu, Bei; Thornton, Charlene Eliza; Tooher, Jane M.; Hennessy, AnnemarieObjective: The increase of soluble VEGF-Receptor 1 (sFlt-1) is thought to contribute to the pathogenesis of preeclampsia. Soluble VEGF-Receptor 1 binds to circulating free VEGF and PLGF and this cascade is associated with endothelial dysfunction, a prominent feature of preeclampsia. Preeclampsia is also associated with excessive maternal response to pro-inflammatory stimuli manifesting as an imbalance of Th1Th2 cytokine production at the maternal-fetal interface. Whether increased sFlt-1 expression has any effect on placental production of Th1Th2 cytokines IL-10 and TNF-? is yet to be investigated. The aim of this study is to examine if exogenous sFlt-1 can regulate Th1Th2 cytokines IL-10 and TNF-? production from normal placental explants via intracellular calcium release.Methods: Placental explants were taken from the decidual surface of normal non-laboured term placentas (n 11).Villous explants were cultured with increasing concentrations of sFlt-1. The dose effect of sFlt-1 on placental Th1 and Th2 cytokine production (TNF-? and IL-10) were examined. Free PLGF, VEGF and sFlt-1 concentrations in the conditioned medium were also measured. Intracellular calcium blocker, 1,2-bis-(o-aminophenoxy)- ethane-N,N,N?,N?-tetraacetic acid, tetra(acetoxymethyl)-ester (BAPTAAM) was applied to investigate whether the changes in cytokine concentration were mediated by intracellular free calcium.Results: Placental IL-10 and TNF-? production were significantly increased after sFlt-1 incubation. The increase in IL-10 can be inhibited by BAPTAAM. Soluble Flt-1 and free PLGF concentration in the conditioned medium was not changed. Free VEGF concentration in the conditioned medium was not detectable.Conclusion: Exogenous sFlt-1 can increase TNF-? and IL-10 production from normal placental explants. The change in Th1Th2 cytokine level may be mediated by intracellular free calcium.
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Chan, Dick C.F.; Watts, Gerald F.; Ooi, Esther M.; Rye, Kerry Anne; Ji, Juying; Johnson, Anthony G.; Barrett, Hugh Hugh R.OBJECTIVE - Subjects with the metabolic syndrome have reduced HDL cholesterol concentration and altered metabolism of high-density lipoprotein (Lp)A-I and LpA-I:A-II particles. In the metabolic syndrome, fenofibrate and atorvastatin may have differential effects on HDL particle kinetics. RESEARCH DESIGN AND METHODS - Eleven men with metabolic syndrome were studied in a randomized, double-blind, crossover trial of 5-week intervention periods with placebo, fenofibrate (200 mg/day), and atorvastatin (40 mg/day). LpA-I and LpA-I:A-II kinetics were examined using stable isotopic techniques and compartmental modeling. RESULTS - Compared with placebo, fenofibrate significantly increased the production of both LpA-I:A-II (30% increase; P < 0.001) and apoA-II (43% increase; P < 0.001), accounting for significant increases of their corresponding plasma concentrations (10 and 23% increases, respectively), but it did not alter LpA-I kinetics or concentration. Atorvastatin did not significantly alter HDL concentration or the kinetics of HDL particles. CONCLUSIONS - In the metabolic syndrome, fenofibrate, but not atorvastatin, influences HDL metabolism by increasing the transport of LpA-I:A-II particles. 2009 by the American Diabetes Association.
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Chan, Dick C.F.; Lambert, Gilles; Barrett, Hugh Hugh R.; Rye, Kerry Anne; Ooi, Esther M.; Watts, Gerald F.BACKGROUND: Experimental studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of LDL metabolism because of its ability to facilitate degradation of the LDL receptor. We investigated the association between plasma PCSK9 concentration and LDL apolipoprotein B-100 (apo B-100) metabolism in men with a wide range of body mass index values. METHODS: Weused GC-MS to study the kinetics of LDL apo B-100 after intravenous administration of deuterated leucine and analyzed the data by compartmental modeling. The plasma PCSK9 concentration was measured by ELISA. RESULTS: Univariate regression analysis revealed the plasma PCSK9 concentration to be significantly and positively correlated with cholesterol (r = 0.543; P = 0.011), LDL cholesterol (r = 0.543; P = 0.011), apo B-100 (r=0.548; P=0.010), and LDL apo B-100 concentrations (r = 0.514; P = 0.023), and inversely correlated with the LDL apo B-100 fractional catabolic rate (FCR) (r = -0.456; P = 0.038). The association between plasma PCSK9 concentration and the LDL apo B-100 FCR remained statistically significant after adjusting for age, obesity, plasma insulin, homeostasis model assessment score, and dietary energy; however, this association had borderline significance after adjusting for plasma lathosterol. CONCLUSIONS: In men, variation in plasma PCSK9 concentration influences the catabolism of LDL apo B-100. This finding appears to be independent of obesity, insulin resistance, energy intake, and age.
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Barter, Philip J.Inhibition of the cholesteryl ester transfer protein (CETP), a plasma protein that normally transfers cholesterol from the protective high-density lipoprotein (HDL) fraction to the atherogenic low-density lipoprotein (LDL) fraction, results in an increase in the concentration of HDL cholesterol and a decrease in the concentration of LDL cholesterol and has been shown in rabbits to inhibit the development of atherosclerosis. The CETP inhibitor torcetrapib was investigated in humans in imaging trials that failed to demonstrate an effect on atheroma in either the carotid or coronary arteries. When tested in a large clinical outcome trial, treatment with torcetrapib was associated with an increase in cardiovascular events and an increase in total mortality. As a result, the development of torcetrapib was terminated. The reason for the adverse effects of torcetrapib is still not known with certainty, but evidence is emerging that these effects may have been the consequence of off-target pharmacologic activity of torcetrapib unrelated to the inhibition of CETP. The potential of CETP inhibition to reduce cardiovascular risk will be determined by the outcome of ongoing clinical trials with CETP inhibitors that do not share the off-target effects of torcetrapib. 2009 Elsevier Inc. All rights reserved.
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Hawkins, Clare L.Hypohalous acids (HOX), produced by peroxidase-catalysed reactions of halide and pseudohalide ions with H2O2, play an important role in the human immune system. However, there is compelling evidence that these oxidants also mediate host tissue damage and contribute to the progression of a number of inflammatory diseases. Although it is well established that significant amounts of hypothiocyanous acid (HOSCN) are formed under physiological conditions, the reactions of this oxidant with host biological systems are relatively poorly characterized. It is generally accepted that HOSCN is a mild oxidant that reacts selectively with thiols. However, it is becoming increasingly recognized that this selectivity can result in the induction of significant cellular damage, which may contribute to disease. This review will outline the formation and reactivity of HOSCN and the role of this oxidant in biological systems.
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Dunlop, Rachael Anne; Brunk, Ulf T.; Rodgers, Kenneth JohnElevated levels of oxidized proteins are reported in diseased tissue from age-related pathologies such as atherosclerosis, neurodegenerative disorders, and cataract. Unlike the precise mechanisms that exist for the repair of nucleic acids, lipids, and carbohydrates, the primary pathway for the repair of oxidized proteins is complete catabolism to their constitutive amino acids. This process can be inefficient as is evidenced by their accumulation. It is generally considered that damaged proteins are degraded by the proteasome; however, this is only true for mildly oxidized proteins, because substrates must be unfolded to enter the narrow catalytic core. Rather, evidence suggests that moderately or heavily oxidized proteins are endocytosed and enter the endosomal/lysosomal system, indicating co-operation between the proteasomes and the lysosomes. Heavily modified substrates are incompletely degraded and accumulate within the lysosomal compartments resulting in the formation of lipofuscin-like, autofluorescent aggregates. Accumulation eventually results in impaired turnover of large organelles such as proteasomes and mitochondria, lysosomal destablization, leakage of proteases into the cytosol and apoptosis. In this review, we summarize reports published since our last assessments of the field of oxidized protein degradation including a role for modified proteins in the induction of apoptosis. 2009 IUBMB.
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Zerrad-Saadi, Amal; Thond, Patrice; Chantepie, Sandrine; Couturier, Martine; Rye, Kerry Anne; Chapman, Martin John; Kontush, Anatol S.OBJECTIVES-: Small dense HDL3 particles of defined lipidome and proteome potently protect atherogenic LDL against free radical-induced oxidation; the molecular determinants of such antioxidative activity in these atheroprotective, antiinflammatory particles remain indeterminate. METHODS AND RESULTS-: Formation of redox-active phosphatidylcholine hydroperoxides (PCOOH) and redox-inactive phosphatidylcholine hydroxides (PCOH) was initiated in LDL by free radical-induced oxidation. Human HDL3 inactivated LDL-derived PCOOH (-62%, P<0.01) and enhanced accumulation of PCOH (2.1-fold, P<0.05); in parallel, HDL3 accumulated minor amounts of PCOOH. Enzyme-deficient reconstituted dense HDL potently inactivated PCOOH (-43%, P<0.01). HDL3-mediated reduction of PCOOH to PCOH occurred concomitantly with oxidation of methionine residues in HDL3-apolipoprotein AI (apoAI). Preoxidation of methionine residues by chloramine T markedly attenuated PCOOH inactivation (-35%); by contrast, inhibition of HDL3-associated enzymes was without effect. PCOOH transfer rates from oxidized LDL to phospholipid liposomes progressively decreased with increment in the rigidity of the phospholipid monolayer. CONCLUSIONS-: The redox status of apoAI and surface lipid rigidity represent major determinants of the potent HDL3-mediated protection of LDL against free radical-induced oxidation. Initial transfer of PCOOH to HDL3 is modulated by the surface rigidity of HDL3 particles with subsequent reduction of PCOOH to PCOH by methionine residues of apoAI. 2009 American Heart Association, Inc.
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Richards, John Brent; Waterworth, Dawn M.; O'Rahilly, Stephen; Hivert, Marie France; Loos, Ruth J.f.; Perry, John R.B.; Tanaka, Toshiko; Timpson, Nicholas J.; Semple, Robert K.; Soranzo, Nicole; Song, Kjioung S.; Rocha, Nuno M.; Grundberg, Elin; Dupuis, Jos; Florez, Jose C.; Langenberg, Claudia C.; Prokopenko, Inga I.; Meitinger, Thomas; Sladek, Robert S.; Aulchenko, Yurii S.; Evans, David M.; Waeber, Gard; Erdmann, Jeanette; Burnett, Mary Susan; Sattar, Naveed A.; Devaney, Joseph M.; Willenborg, Christina; Hingorani, Aroon Dinesh; Witteman, Jacqueline C.M.; Vollenweider, Peter K.; St Pourcain, Beate; Hengstenberg, Christian; Ferrucci, Luigi G.; Melzer, David; Stark, Klaus J.; Deanfield, John Eric; Winogradow, Janina; Grassl, Martina; Hall, Alistair Scott; Egan, Josephine M.; Thompson, John R.; Ricketts, Sally L.; Kig, I. R.; Reinhard, Wibke; Grundy, Scott M.; Wichmann, Heinz-Erich Erich; Barter, Philip J.; Mahley, Robert W.; Kesaniemi, YrjAntero; Rader, Daniel J.; Reilly, Muredach P.; Epstein, Stephen E.; Stewart, Alexandre F.R.; van Duijn, Cornelia M.; Schunkert, Heribert; Burling, Keith A.; Deloukas, Panos; Pastinen, Tomi M.; Samani, Nilesh J.; McPherson, Ruth M.; Davey Smith, George; Frayling, Tim M.; Wareham, Nicholas J.; Meigs, James B.; Mooser, Vincent E.; Spector, Tim DavidThe adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P?50-8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P?0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.20-19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.90-8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.50-6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.20-3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk. 2009 Richards et al.
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Barter, Philip J.[No abstract available]
