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Showing 1461–1480 of 2058 publications.
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Stanley, Naomi R.; Stadler, Nadina; Woods, Alan A.; Bannon, Paul Gerard; Davies, Michael J.Previous studies have provided compelling evidence for the presence of oxidized proteins and lipids in advanced human atherosclerotic lesions. The catalyst responsible for such oxidation is unknown and controversial. We have previously provided evidence for elevated levels of iron in lesions. In this study we hypothesized that if iron ions catalyzed protein and lipid oxidation in the artery wall, then there should be a positive correlation between these parameters. Iron concentrations in ex vivo healthy human arteries and advanced carotid lesions were quantified by electron paramagnetic resonance spectroscopy. Four specific side-chain oxidation products of proteins, and the lipid oxidation products 7-ketocholesterol and cholesterol ester alcohols and hydroperoxides, were quantified by HPLC in the same samples used for the iron measurements. Parent amino acids, cholesterol, and cholesterol esters were also quantified. Statistically elevated levels of iron, cholesterol, cholesterol esters, 7-ketocholesterol, and cholesterol ester alcohols and hydroperoxides were detected in advanced lesions compared with healthy control tissue. Iron levels correlated positively and strongly with all four markers of protein oxidation, but not with either marker of lipid oxidation. These data support the hypothesis that elevated levels of iron contribute to the extent of protein, but not lipid, oxidation in advanced human lesions. 2006 Elsevier Inc. All rights reserved.
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Gelissen, Ingrid C.; Harris, Matthew J.; Rye, Kerry Anne; Quinn, Carmel M.; Brown, Andrew J.; Kockx, Maae; Cartland, Si; Packianathan, Mathana; Kritharides, Leonard; Jessup, Wendy K.Objective - To study the acceptor specificity for human ABCG1 (hABCG1)-mediated cholesterol efflux. Methods and Results - Cells overexpressing hABCG1 were created in Chinese Hamster Ovary (CHO-K1) cells and characterized in terms of lipid composition. hABCG1 expressed in these cells formed homodimers and was mostly present intracellularly. Cholesterol efflux from hABCG1 cells to HDL<inf>2</inf> and HDL<inf>3</inf> was increased but not to lipid-free apolipoproteins. A range of phospholipid containing acceptors apart from high-density lipoprotein (HDL) subclasses were also efficient in mediating ABCG1-dependent export of cholesterol. Importantly, a buoyant phospholipid-containing fraction generated from incubation of lipid-free apoA-I with macrophages was nearly as efficient as HDL<inf>2</inf>. The capacity of acceptors to induce ABCG1-mediated efflux was strongly correlated with their total phospholipid content, suggesting that acceptor phospholipids drive ABCG1-mediated efflux. Most importantly, acceptors for ABCG1-mediated cholesterol export could be generated from incubation of cells with lipid-free apoA-I through the action of ABCA1 alone. Conclusions - These results indicate a synergistic relationship between ABCA1 and ABCG1 in peripheral tissues, where ABCA1 lipidates any lipid-poor/free apoA-I to generate nascent or pre-?-HDL. These particles in turn may serve as substrates for ABCG1-mediated cholesterol export. 2006 American Heart Association, Inc.
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Rees, Martin D.; Davies, Michael J.The highly basic heme enzyme myeloperoxidase (MPO), which is released by activated phagocytes, catalyzes the production of the potent oxidant hypochlorite (HOCI) from H<inf>2</inf>O<inf>2</inf> and chloride ions (Cl -). Heparan sulfate proteoglycans are key components of the extracellular matrix and cell surfaces and are known to bind MPO avidly via their negatively charged heparan sulfate chains. Reaction of heparan sulfate with HOCI generates polymer-derived N-chloro derivatives (chloramines, dichloramines, N-chlorosulfonamides, and chloramides). In this study, it is shown that heparan sulfate N-chloro derivatives are decomposed in the presence of redox-active transition-metal ions and superoxide (O<inf>2</inf> .-). These processes initiate polymer modification/fragmentation. Radical intermediates in these processes have been identified by EPR spectroscopy and spin trapping. Evidence has been obtained that the N-chloro derivatives undergo reductive homolysis to nitrogen-centered (aminyl, N-chloroaminyl, sulfonamidyl, and amidyl) radicals that generate carbon-centered radicals via rapid, intramolecular hydrogen atom abstraction reactions (1,2-and/or 1,5-shifts). In the case of the sulfonamidyl radicals, rearrangement via 1,2-shifts and ?-scission of the resultant C-2 carbon-centered radicals to yield SO<inf>3</inf>.- and C-2 imines is near quantitative based on the yield of SO<inf>4</inf>2-, the decomposition product of SO<inf>3</inf>.-. The formation of strand breaks and chromophores during these reactions is attributed to the formation and subsequent heterolytic rearrangement of the C-2 imines. The degradation of heparan sulfate via reductive homolysis of its N-chloro derivatives may be of significance at sites of inflammation, where MPO-derived HOCI is produced in high concentration and transition-metal ions and O<inf>2</inf>.- are known to be present or generated. 2006 American Chemical Society.
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Lau, Antony K.; Chaufour, Xavier; McLachlan, Craig Steven; Leichtweis, Steve B.; Celermajer, David S.; Sullivan, Collin E.; Stocker, RolandHypoxia increases and hyperoxia decreases experimental atherosclerosis, but it is unclear if repetitive hypoxic and hyperoxic insults affect intimal thickening after arterial injury. Rabbits on 2% cholesterol diet for 6 weeks underwent balloon injury to the abdominal aorta (AA) after week 3, and were then exposed to normoxia (n = 6), or 12 h daily of intermittent repetitive hypoxia (n = 6) or hyperoxia (n = 6). After week 6, damaged AA and undamaged thoracic aorta (TA) were assessed for intimal thickening and lipid content. Compared with normoxia, hypoxia and hyperoxia did not alter the rise in serum cholesterol related to cholesterol feeding. However, compared to normoxia, hypoxia markedly increased the intima-to-media ratio in AA (1.18 0.09 versus 1.96 0.14, P < 0.01) and TA (0.15 0.02 versus 0.41 0.01, P < 0.01) whereas hyperoxia had no effect on AA disease and increased intimal thickening in TA (0.26 0.03, P < 0.01). Hyperoxia promoted positive arterial remodeling in both TA and AA, resulting in larger luminal size. The cholesterol content in AA was increased by hypoxia and decreased by hyperoxia, but decreased by both treatments in TA. Lipophilic antioxidants and the proportion of arterial lipids that was oxidized were not altered by hypoxia or hyperoxia. These results suggest that intermittent repetitive hyperoxia is not protective and intermittent repetitive hypoxia promotes arterial disease in normal and injured arteries independent of lipid peroxidation. 2005 Elsevier Ireland Ltd. All rights reserved.
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Brown, Bronwyn E.; Mahroof, F. M.; Cook, Naomi L.; Van Reyk, David M.; Davies, Michael J.Aims/hypothesis: Previous studies have shown that glycation of LDL by methylglyoxal and glycolaldehyde, in the absence of significant oxidation, results in lipid accumulation in macrophage cells. Such 'foam cells' are a hallmark of atherosclerosis. In this study we examined whether LDL glycation by methylglyoxal or glycolaldehyde, and subsequent lipid loading of cells, can be inhibited by agents that scavenge reactive carbonyls. Such compounds may have therapeutic potential in diabetes-associated atherosclerosis. Materials and methods: LDL was glycated with methylglyoxal or glycolaldehyde in the absence or presence of metformin, aminoguanidine, Girard's reagents P and T, or hydralazine. LDL modification was characterised by changes in mobility (agarose gel electrophoresis), cross-linking (SDS-PAGE) and loss of amino acid residues (HPLC). Accumulation of cholesterol and cholesteryl esters in murine macrophages was assessed by HPLC. Results: Inhibition of LDL glycation was detected with equimolar or greater concentrations of the scavengers over the reactive carbonyl. This inhibition was structure-dependent and accompanied by a modulation of cholesterol and cholesteryl ester accumulation. With aminoguanidine, Girard's reagent P and hydralazine, cellular sterol levels returned to control levels despite incomplete inhibition of LDL modification. Conclusions/ interpretation: Inhibition of LDL glycation by interception of the reactive aldehydes that induce LDL modification prevents lipid loading and model foam cell formation in murine macrophage cells. Carbonyl-scavenging reagents, such as hydrazines, may therefore help inhibit LDL glycation in vivo and prevent diabetes-induced atherosclerosis. Springer-Verlag 2006.
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Makris, Angela; Xu, Bei; Yu, Bing; Thornton, Charlene Eliza; Hennessy, AnnemarieThe placenta is pivotal in the acceptance of the feto-placental unit by the maternal immune system. Imbalance at the maternal-fetal interface of tissue pro- and anti-inflammatory cytokines may be partly involved in disease causation. Previous work has shown conflicting levels of IL-10. IL-10 levels have been shown to increase, decrease, or remain unchanged in women with preeclampsia. This study examines the difference in serum and placental IL-10 expression in women with preeclampsia and investigates if the IL10 (-1082) A promoter polymorphism contributes to lower concentrations. In a prospective case-control study of 12 women with preeclampsia and 31 controls we assessed serum IL-10 by ELISA, placental mRNA by quantitative PCR and protein by immunohistochemistry as well as placental IL10 promoter genotype. Comparisons were made with non-parametric tests where necessary and chi-square. We found a significant reduction in placental IL-10 mRNA and protein expression in women with preeclampsia compared to controls. Women with the AA IL-10 promoter genotype expressed less placental IL-10 mRNA compared to women with AG or GG genotype. There was no difference in serum IL-10 concentrations between different genotypes. Preeclampsia is associated with a deficiency of placental IL-10. Placental AA genotype in the promoter region results in significantly less placental IL-10. 2005 Elsevier Ltd. All rights reserved.
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Kee, Patrick H.; Caiazza, Daniela; Rye, Kerry Anne; Barrett, Hugh Hugh R.; Morehouse, Lee A.; Barter, Philip J.Objective - Inhibitors of cholesteryl ester transfer protein (CETP) have been developed as potential anti-atherogenic agents. Theoretically, however, they may be pro-atherogenic by blocking one of the pathways for removing high-density lipoprotein (HDL) cholesteryl esters (CE) from plasma in the final step of reverse cholesterol transport. Here we describe how CETP inhibition in rabbits impacts on the kinetics of HDL CE transport in plasma. Methods and Results - Administration of a CETP inhibitor reduced CETP activity by 80% to 90% and doubled the HDL cholesteryl ester concentration. Multi-compartmental analysis was used to determine HDL CE kinetics in CETP-inhibited and control rabbits after injection of tracer amounts of both native and reconstituted HDL labeled with 3H in the CE moiety. In control rabbits, HDL CE was removed from plasma by both a direct pathway and an indirect pathway after transfer of HDL CE to the very-low-density lipoprotein/low-density lipoprotein fraction. In CETP-inhibited rabbits there was an almost complete block in removal via the indirect pathway. This did not compromise the overall removal of HDL CE from plasma, which was not different in control and inhibited animals. Conclusion - Inhibiting CETP in rabbits does not compromise the removal of HDL CE from plasma. 2006 American Heart Association, Inc.
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Rodgers, Kenneth John; Watkins, Deborah J.; Miller, Alastair L.; Chan, Peter Y.; Karanam, Sharada; Brissette, William H.; Long, Clive J.; Jackson, Christopher LangdaleObjective - Lysosomal proteinases have been implicated in a number of pathologies associated with extracellular matrix breakdown. Therefore, we investigated the possibility that the lysosomal proteinase cathepsin S may be involved in atherosclerotic plaque destabilization. Methods and Results - Atherosclerotic plaques in the brachiocephalic arteries of fat-fed apolipoprotein E/cathepsin S double knockout mice had 73% fewer acute plaque ruptures (P=0.026) and were 46% smaller (P=0.025) than those in age-, strain-, and sex-matched apolipoprotein E single knockout controls. When the incidence of acute plaque rupture was normalized for plaque size, the reduction in the double knockouts was 72% (P=0.039). The number of buried fibrous layers, indicative of an unstable plaque phenotype, was reduced by 67% in the double knockouts (P=0.008). The cysteine proteinase inhibitor, egg white cystatin, was biotinylated and used as an active-site-directed probe for cathepsins. Biotinylated cystatin selectively detected cathepsin S in extracts of human carotid atherosclerotic plaque. Active cathepsin S was detectable in extracts of human atherosclerotic plaque but not in nondiseased carotid arteries. Active cathepsins were especially prominent in macrophages in the shoulder regions of plaques, areas considered to be vulnerable to rupture. Cathepsin S protein colocalized with regions of elastin degradation in human coronary plaques. Conclusion - These data provide direct evidence that an endogenous proteinase, cathepsin S, plays an important role in atherosclerotic plaque destabilization and rupture. 2006 American Heart Association, Inc.
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Malle, Ernst; Marsche, Gunther; Arnhold, Jgen; Davies, Michael J.Substantial evidence supports the notion that oxidative processes contribute to the pathogenesis of atherosclerosis and coronary heart disease. The nature of the oxidants that give rise to the elevated levels of oxidised lipids and proteins, and decreased levels of antioxidants, detected in human atherosclerotic lesions are, however, unclear, with multiple species having been invoked. Over the last few years, considerable data have been obtained in support of the hypothesis that oxidants generated by the heme enzyme myeloperoxidase play a key role in oxidation reactions in the artery wall. In this article, the evidence for a role of myeloperoxidase, and oxidants generated therefrom, in the modification of low-density lipoprotein, the major source of lipids in atherosclerotic lesions, is reviewed. Particular emphasis is placed on the reactions of the reactive species generated by this enzyme, the mechanisms and sites of damage, the role of modification of the different components of low-density lipoprotein, and the biological consequences of such oxidation on cell types present in the artery wall and in the circulation, respectively. 2006 Elsevier B.V. All rights reserved.
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Barter, Philip J.; Rye, Kerry AnneAn inverse relationship between the concentration of high-density lipoprotein (HDL) cholesterol and the risk of developing cardiovascular is well established. There are several documented functions of HDLs that may contribute to a protective role of these lipoproteins. These include the ability of HDLs to promote the efflux of cholesterol from macrophages and foam cells in the artery wall and to anti-inflammatory/antioxidant properties of these lipoproteins. The fact that the main apolipoprotein of HDLs, apoA-I, plays a prominent role in each of these functions adds support to the view that apoA-I should be measured as a component of the assessment of cardiovascular risk in humans. 2006 Blackwell Publishing Ltd.
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Inhibition of H-Ras and MAPK is compensated by PKC-dependent pathways in annexin A6 expressing cellsRentero, Carles; Evans, Rachel; Wood, Peta; Tebar, Francesc; Vilde Muga, Sandra; Cubells, Laia Garrigos; de Diego, Iki; Hayes, Toni E.; Hughes, William E.; Pol, Albert; Rye, Kerry Anne; Enrich, Carlos; Grewal, ThomasHigh-density lipoprotein (HDL)-induced activation of the Ras/MAPK pathway can be mediated by protein kinase C (PKC)-dependent and independent pathways. Although both pathways co-exist in cells, we showed that binding of HDL to scavenger receptor BI (SR-BI) in CHO cells activates Ras and MAPK in a PKC-independent manner. We have recently identified that HDL-induced activation of Ras and Raf-1 is reduced in annexin A6 expressing CHO cells (CHOanx6). In the present study we demonstrate that despite the loss of Ras and Raf-1 activity, HDL induces MAPK phosphorylation in CHOanx6 cells. Since annexin A6 is a PKC?-binding protein we therefore investigated the possible involvement of PKC in HDL-induced Ras and MAPK activation in CHOanx6 cells. Taken together our findings demonstrate that HDL-induced H-Ras and MAPK activation is PKC-dependent in cells expressing annexin A6 to compensate for the loss of PKC-independent activation of H-Ras and MAPK. 2005 Elsevier Inc. All rights reserved.
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Headlam, Henrietta A.; Gracanin, Michelle; Rodgers, Kenneth John; Davies, Michael J.Reaction of radicals in the presence of O<inf>2</inf>, and singlet oxygen, with some amino acids, peptides, and proteins yields hydroperoxides. These species are key intermediates in chain reactions and protein damage. Previously we have shown that peptide and protein hydroperoxides react rapidly with thiols, and that this can result in inactivation of thiol-dependent enzymes. The major route for the cellular removal of damaged proteins is via catabolism mediated by proteosomal and lysosomal pathways; cysteine proteases (cathepsins) play a key role in the latter system. We hypothesized that inactivation of cysteine proteases by hydroperoxide-containing oxidised proteins may contribute to the accumulation of modified proteins within cells. We show here that thiol-dependent cathepsins, either isolated or in cell lysates, are rapidly and efficiently inactivated by amino acid, peptide, and protein hydroperoxides in a time- and concentration-dependent manner; this occurs with similar efficacy to equimolar H<inf>2</inf>O<inf>2</inf>. Inactivation involves reaction of the hydroperoxide with Cys residues as evidenced by thiol loss and formation of sulfenic acid intermediates. Structurally related, non-thiol-dependent cathepsins are less readily inactivated by these hydroperoxides. This inhibition, by oxidized proteins, of the system designed to remove modified proteins, may contribute to the accumulation of damaged proteins in cells subject to oxidative stress. 2006 Elsevier Inc. All rights reserved.
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Tremblay, AndrJ.; Lamarche, Beno ?t; Cohn, Jeffrey S.; Hogue, Jean Charles; Couture, PatrickObjective - To examine the impact of ezetimibe, a selective inhibitor of intestinal cholesterol absorption, on the in vivo kinetics of apolipoproteins (apo) B-48 and B-100 in humans. Methods and Results - Kinetics of triglyceride-rich lipoprotein (TRL) apoB-48 and very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB-100 labeled with a stable isotope were assessed at baseline and at the end of 8 weeks of treatment with 10 mg/d of ezetimibe in 8 men with moderate primary hypercholesterolemia. Data were fit to a multicompartmental model using SAAMII to calculate fractional catabolic rate (FCR) and production rate (PR). Ezetimibe significantly decreased total and LDL cholesterol concentrations by -14.5% and -22.0% (P=0.004), respectively, with no significant change in plasma triglyceride and high-density lipoprotein (HDL) cholesterol levels. Ezetimibe had no significant effect on TRL apoB-48 kinetics and pool size (PS). However, VLDL and IDL apoB-100 FCRs were significantly increased (+31.2%, P=0.02 and +20.8%, P=0.04, respectively) with a concomitant elevation of VLDL apoB-100 PR (+20.9%, P=0.04). Furthermore, LDL apoB-100 PS was significantly reduced by -23.2% (P=0.004), caused by a significant increase in FCR of this lipoprotein fraction (+24.0%, P=0.04). Conclusions - These results indicate that reduction of plasma LDL cholesterol concentration after treatment with ezetimibe is associated with an increase in FCR of apoB-100-containing lipoproteins. 2006 American Heart Association, Inc.
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Tso, Colin; Martinic, Gary; Fan, Wenhua; Rogers, Campbell David K.; Rye, Kerry Anne; Barter, Philip J.Objective - We quantified endothelial progenitor cell (EPC) engraftment into the endothelial layer as an index of progenitor-mediated endothelial repair. Studies were conducted in C57BL/6J and in apolipoprotein E-deficient (apoE-/-) mice. We also investigated the possibility that high-density lipoproteins (HDL) may promote progenitor-mediated endothelial repair. Methods and Results - Thoracic aortic sections from C57BL/6J and apoE-/- mice were analyzed for evidence of progenitor-derived endothelium as determined by the number of stem cell antigen-1-positive (Sca-1+) cells in the endothelial layer. EPCs (Sca-1+ cells) were significantly increased after endothelial damage induced by lipopolysaccharide (LPS) administration in C57BL/6J mice. The number of EPCs was greater in the aortic endothelium of untreated apoE-/- than in untreated C57BL/6J mice and was similar to the number observed in LPS-treated C57BL/6J mice. The number of EPCs in the aortic endothelium of apoE-/- mice more than doubled after intravenous infusion of reconstituted HDL. Conclusions - EPCs are recruited into the aortic endothelial layer of mice in response to an inflammatory insult. EPCs are also increased in the aortic endothelium of untreated apoE-/- mice. The observation that number is further increased in apoE-/- mice after injection of HDL suggests a role for HDL in promoting progenitor-mediated endothelial repair. 2006 American Heart Association, Inc.
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Rye, Kerry Anne; Bright, Richard J.; Psaltis, Maria K.; Barter, Philip J.Apolipoprotein E (apoE) enters the plasma as a component of discoidal HDL and is subsequently incorporated into spherical HDL, most of which contain apoE as the sole apolipoprotein. This study investigates the regulation, origins, and structure of spherical, apoE-containing HDLs and their remodeling by cholesteryl ester transfer protein (CETP). When the ability of discoidal reconstituted high density lipoprotein (rHDL) containing apoE2 [(E2)rHDL], apoE3 [(E3)rHDL], or apoE4 [(E4)rHDL] as the sole apolipoprotein to act as substrates for LCAT were compared with that of discoidal rHDL containing apoA-I [(A-I)rHDL], the rate of cholesterol esterification was (A-I)rHDL ? (E2)rHDL ? (E3)rHDL > (E4)rHDL. LCAT also had a higher affinity for discoidal (A-I)rHDL than for the apoE-containing rHDL. When the discoidal rHDLs were incubated with LCAT and LDL, the resulting spherical (E2)rHDL, (E3)rHDL, and (E4)rHDL were larger than, and structurally distinct from, spherical (A-I)rHDL. Incubation of the apoE-containing spherical rHDL with CETP and Intralipid generated large fusion products without the dissociation of apoE, whereas the spherical (A-I)rHDLs were remodeled into small particles with the formation of lipid-poor apoA-I. In conclusion, i) apoE activates LCAT less efficiently than apoA-I; ii) apoE-containing spherical rHDLs are structurally distinct from spherical (A-I)rHDL; and iii) the CETP-mediated remodeling of apoE-containing spherical rHDL differs from that of spherical (A-I)rHDL. Copyright 2006 by the American Society for Biochemistry and Molecular Biology, Inc.
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He, Zhicong; Aristoteli, Lina Panayiota; Kritharides, Leonard; Garner, BrettGlycosylation is a common but variable modification that regulates glycoprotein structure and function. We combined small format 2D-PAGE with HPLC to analyse discrete human haptoglobin isoform N-glycans. Seven major and several minor haptoglobin isoforms were detected by 2D-PAGE. N-Glycans released from Coomassie-stained gel spots using PNGase were labeled at their reducing termini with 2-aminobenzamide. HPLC analysis of selected major isoform N-glycans indicated that sialic acid composition determined their separation by isoelectric focussing. N-Glycans from two doublets of quantitatively minor isoforms were also analysed. Although separation of each pair of doublets was influenced by sialylation, individual spots within each doublet contained identical N-glycans. Thus, heterogeneity in minor haptoglobin isoforms was due to modifications distinct from N-glycan structure. These studies describe a simple method for analysing low abundance protein N-glycans and provide details of discrete haptoglobin isoform N-glycan structures which will be useful in proteomic analysis of human plasma samples. 2006 Elsevier Inc. All rights reserved.
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Watts, Ralph Neal; Hawkins, Clare L.; Po?ka, Prem; Richardson, Des RaymondNitrogen monoxide (NO) plays a role in the cytotoxic mechanisms of activated macrophages against tumor cells by inducing iron (Fe) release. We have shown that NO-mediated Fe efflux from cells required glutathione (GSH), and we have hypothesized that a GS-Fe-NO complex was released. Hence, we studied the role of the GSH-conjugate transporter multidrug resistance-associated protein 1 (MRP1) in NO-mediated Fe efflux. MCF7-VP cells overexpressing MRP1 exhibited a 3- to 4-fold increase in NO-mediated 59Fe and GSH efflux compared with WT cells (MCF7-WT) over 4 h. Similar results were found for other MRP1-overexpressing cell types but not those expressing another drug efflux pump, P-glycoprotein. NO-mediated 59Fe and GSH efflux were temperature- and energy-dependent and were significantly decreased by the GSH-depleting agent and MRP1 transport inhibitor L-buthionine-[S,R]-sulfoximine. Other MRP1 inhibitors, MK571, probenecid, and difloxacin, significantly inhibited NO-mediated 59Fe release. EPR spectroscopy demonstrated the dinitrosyl-dithiol-Fe complex (DNIC) peak in NO-treated cells was increased by MRP1 inhibitors, indicating inhibited DNIC transport from cells. The extent of DNIC accumulation correlated with the ability of MRP1 inhibitors to prevent NO-mediated 59Fe efflux. MCF7-VP cells were more sensitive than MCF7-WT cells to growth inhibition by effects of NO, which was potentiated by L-buthionine-[S,R]-sulfoximine. These data indicate the importance of GSH in NO-mediated inhibition of proliferation. Collectively, NO stimulates Fe and GSH efflux from cells via MRP1. Active transport of NO by MRP1 overcomes diffusion that is inefficient and nontargeted, which has broad ramifications for understanding NO biology. 2006 by The National Academy of Sciences of the USA.
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Barter, Philip J.; Rye, Kerry Anne[No abstract available]
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Duez, He; Lamarche, Beno ?t; Uffelman, Kristine D.; Valo, Ren Cohn, Jeffrey S.; Lewis, Gary FranklinOBJECTIVES - Whereas postprandial hyperlipidemia is a well-described feature of insulin-resistant states and type 2 diabetes, no previous studies have examined intestinal lipoprotein production rates (PRs) in relation to hyperinsulinemia or insulin resistance in humans. METHODS AND RESULTS - Apolipoprotein B-48 (apoB-48)-containing lipoprotein metabolism was examined in the steady-state fed condition with a 15-hour primed constant infusion of [D3]-l-leucine in 14 nondiabetic men with a broad range of body mass index (BMI) and insulin sensitivity. To examine the relationship between indices of insulin resistance and intestinal lipoprotein PR data were analyzed in 2 ways: by correlation and by comparing apoB-48 PRs in those whose fasting plasma insulin concentrations were above or below the median for the 14 subjects studied (60 pmol/L). ApoB-48 PR was significantly higher in hyperinsulinemic, insulin-resistant subjects (1.730.39 versus 0.880.13 mg/kg per day; P<0.05) and correlated with fasting plasma insulin concentrations (r=0.558; P=0.038), despite great heterogeneity in apoB-48 kinetic parameters, particularly among the obese subjects. There was no significant difference in clearance of apoB-48 between the 2 groups, nor was there a significant correlation between apoB-48 fractional clearance rate and fasting insulin or homeostasis model assessment-insulin resistance. CONCLUSIONS - These are the first human data to conclusively demonstrate that intestinal apoB-48-containing triglyceride-rich lipoprotein PR is increased in hyperinsulinemic, insulin-resistant humans. Intestinal lipoprotein particle overproduction is a newly described feature of insulin resistance in humans. 2006 American Heart Association, Inc.
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Agon, Vanessa V.; Bubb, William A.; Wright, Adam; Hawkins, Clare L.; Davies, Michael J.[No abstract available]
