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Showing 1141–1160 of 2058 publications.
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Cook, Naomi L.; Viola, Helena M.; Sharov, Victor S.; Hool, Livia C.; Scheich, Christian S.; Davies, Michael J.The sarco/endoplasmic reticulum Ca 2 +-ATPase (SERCA) plays a critical role in Ca 2 + homeostasis via sequestration of this ion in the sarco/endoplasmic reticulum. The activity of this pump is inhibited by oxidants and impaired in aging tissues and cardiovascular disease. We have shown previously that the myeloperoxidase (MPO)-derived oxidants HOCl and HOSCN target thiols and mediate cellular dysfunction. As SERCA contains Cys residues critical to ATPase activity, we hypothesized that HOCl and HOSCN might inhibit SERCA activity, via thiol oxidation, and increase cytosolic Ca 2 + levels in human coronary artery endothelial cells (HCAEC). Exposure of sarcoplasmic reticulum vesicles to preformed or enzymatically generated HOCl and HOSCN resulted in a concentration-dependent decrease in ATPase activity; this was also inhibited by the SERCA inhibitor thapsigargin. Decomposed HOSCN and incomplete MPO enzyme systems did not decrease activity. Loss of ATPase activity occurred concurrent with oxidation of SERCA Cys residues and protein modification. Exposure of HCAEC, with or without external Ca 2 +, to HOSCN or HOCl resulted in a time-and concentration-dependent increase in intracellular Ca 2 + under conditions that did not result in immediate loss of cell viability. Thapsigargin, but not inhibitors of plasma membrane or mitochondrial Ca 2 + pumps/channels, completely attenuated the increase in intracellular Ca 2 + consistent with a critical role for SERCA in maintaining endothelial cell Ca 2 + homeostasis. Angiotensin II pretreatment potentiated the effect of HOSCN at low concentrations. MPO-mediated modulation of intracellular Ca 2 + levels may exacerbate endothelial dysfunction, a key early event in atherosclerosis, and be more marked in smokers because of their higher SCN - levels. 2011 Elsevier Inc. All rights reserved.
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Yazbek, Roger; Dawson, P.; Rogers, N.; West, C.; Keogh, R.; Wallace, Daniel F.; Polyak, Steven W.; Nowak, Kristen J.; Burt, R.; Taylor, John; Dunn, Louise L.; Philp, A.; Parkinson-Lawrence, Emma J.The 50th annual National Scientific Conference of the Australian Society for Medical Research was held in Cairns, Queensland, 13-16 November 2011. The theme, 'Indigenous Health: ACTION on Prevention' highlighted the direct action being undertaken by health and medical researchers, as well as allied health professionals, to improve long-term health outcomes for Indigenous Australians. R Yazbeck, P Dawson, N Rogers, C West, R Keogh, D Wallace, S Polyak, K Nowak, R Burt, J Taylor, L Dunn, A Philp, E Parkinson-Lawrence, 2012.
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Lok, Hiu Chuen; Suryo Rahmanto, Yohan; Hawkins, Clare L.; Kalinowski, Danuta S.; Morrow, Charles S.; Townsend, Alan J.; Po?ka, Prem; Richardson, Des RaymondNitrogen monoxide (NO) plays a role in the cytotoxic mechanisms of activated macrophages against tumor cells by inducing iron release. We showed that NO-mediated iron efflux from cells required glutathione (GSH) (Watts, R. N., and Richardson, D. R. (2001) J. Biol. Chem. 276, 4724-4732) and that the GSH-conjugate transporter, multidrug resistance-associated protein 1 (MRP1), mediates this release potentially as a dinitrosyl-dithiol iron complex (DNIC; Watts, R. N., Hawkins, C., Ponka, P., and Richardson, D. R. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 7670-7675). Recently, glutathione S-transferase P1-1 (GST P1-1) was shown to bind DNICs as dinitrosyl-diglutathionyl iron complexes. Considering this and that GSTs and MRP1 form an integrated detoxification unit with chemotherapeutics, we assessed whether these proteins coordinately regulate storage and transport of DNICs as long lived NO intermediates. Cells transfected with GSTP1 (but not GSTA1 or GSTM1) significantly decreased NO-mediated 59Fe release from cells. This NO-mediated 59Fe efflux and the effect of GST P1-1 on preventing this were observed with NO-generating agents and also in cells transfected with inducible nitric oxide synthase. Notably, 59Fe accumulated in cells within GST P1-1-containing fractions, indicating an alteration in intracellular 59Fe distribution. Furthermore, electron paramagnetic resonance studies showed that MCF7-VP cells transfected with GSTP1 contain significantly greater levels of a unique DNIC signal. These investigations indicate that GST P1-1 acts to sequester NO as DNICs, reducing their transport out of the cell by MRP1. Cell proliferation studies demonstrated the importance of the combined effect of GST P1-1 and MRP1 in protecting cells from the cytotoxic effects of NO. Thus, the DNIC storage function of GST P1-1 and ability of MRP1 to efflux DNICs are vital in protection against NO cytotoxicity. 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
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Wu, Ben Jing; Chen, Kang; Barter, Philip J.; Rye, Kerry AnneBackground-: Heme oxygenase-1 (HO-1) is a cytoprotective protein whose expression is consistently associated with therapeutic benefits in a number of pathological conditions such as atherosclerotic vascular disease and inflammation. Niacin is a pleiotropic drug that slows the progression of coronary artery disease and increases serum levels of the HO-1 enzymatic product bilirubin. This study asks if the cardioprotective properties of niacin involve the induction of HO-1. Methods and Results-: New Zealand White rabbits received chow or chow supplemented with 0.6% (wt/wt) niacin for 2 weeks. Acute vascular inflammation was induced in the animals by placing a nonocclusive silastic collar around the left common carotid artery. At 24 hours after collar implantation, serum bilirubin and vascular, liver, and spleen HO-1 messenger RNA levels were significantly increased. Vascular inflammation was decreased in the niacin-supplemented animals compared with control. Treatment of the animals with tin protoporphyrin-IX, a global HO inhibitor, or HO-1 small interfering RNA to knock down carotid artery HO-1 attenuated the ability of niacin to inhibit vascular inflammation. Treatment of cultured human coronary artery endothelial cells with niacin increased HO-1 expression by activating the nuclear factor-E2-related factor 2/p38 mitogen-activated protein kinase signaling pathway and inhibiting tumor necrosis factor ?-induced endothelial inflammation. The antiinflammatory effects of niacin in human coronary artery endothelial cells were mimicked by bilirubin and abolished by incubation with tin protoporphyrin-IX and knock down of nuclear factor-E2-related factor 2. Conclusions-: Niacin activates HO-1 in vivo and in vitro. Induction of HO-1 may be partly responsible for the vascular protective properties of niacin. 2011 American Heart Association, Inc.
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Palmer, Nicholette (Nichole); McDonough, Caitrin W.; Hicks, Pamela J.; Roh, Bong H.; Wing, Maria R.; An, S. Sandy; Hester, Jessica M.; Cooke-Bailey, Jessica N.; Bostrom, Meredith A.; Rudock, Megan E.; Talbert, Matthew E.; Lewis, Joshua P.; Ferrara, Assiamira M.; Lu, Lingyi; Ziegler, Julie T.; Sale, Miche M.; Divers, Jasmin; Shriner, Daniel A.; Adeyemo, Adebowale A.; Rotimi, Charles N.; Ng, Maggie Chor Yin; Langefeld, Carl D.; Freedman, Barry I.; Bowden, Donald W.; Voight, Benjamin F.; Scott, Laura J.; Steinthsdtir, Valgerdur; Morris, Andrew Paul; Dina, Christian; Welch, Ryan P.; Zeggini, Eleftheria; Huth, Cornelia; Aulchenko, Yurii S.; Thorleifs-Son, Gudmar; McCulloch, Laura J.; Ferreira, Teresa; Grallert, Harald; Amin, Najaf A.; Wu, Guanming R.; Willer, Cristen J.; Raychaudhuri, Soumya; McCarroll, Steven A.; Langenberg, Claudia C.; Hofmann, Oliver M.; Dupuis, Jos; Qi, Lu; Segr Ayellet V.; van Hoek, Mandy; Navarro, Pau; Ardlie, Kristin G.; Balkau, Beverley J.; Benediktsson, Rafn; Bennett, Amanda J.; Blagieva, Roza; Boerwinkle, Eric A.; Bonnycastle, Lori L.; Bengtsson-Bostr, Kristina; Bravenboer, Bert; Bumpstead, Suzannah J.; Burtt, Nl P.; Charpentier, Guillaume; Chines, Peter S.; Cornelis, Marylin C.; Couper, David J.; Crawford, Gabriel J.; Doney, Alex S.F.; Elliott, Katherine S.; Elliott, Amanda L.; Erdos, Michael R.; Fox, Caroline S.; Franklin, Christopher S.; Ganser, Martha A.; Gieger, Christian; Grarup, Niels; Green, Todd; Griffin, Simon J.; Groves, Christopher James; Guiducci, Candace; Hadjadj, Samy; Hassanali, Neelam; Herder, Christian; Isomaa, Bo A.; Jackson, Anne U.; Johnson, Paul R.V.; Jgensen, Torben J.; Linda Kao, Wen Hong Linda; Klopp, Norman; Kong, Augustine S.; Kraft, Peter P.; Kuusisto, Johanna K.; Lauritzen, Torsten; Li, Man; Lieverse, Aloysius G.; Lindgren, Cecilia M.; Lyssenko, Valeriya; Marre, Michel; Meitinger, Thomas A.; Mid-Thjell, Kristian; Morken, Mario A.; Narisu, Narisu; Nilsson, Peter M.; Owen, Katharine R.; Payne, Felicity; Perry, John R.B.; Petersen, Ann Kristin; Platou, Carl G.P.; Proen, Christine; Prokopenko, Inga I.; Rathmann, Wolfgang G.; Rayner, Nigel William; Robertson, Neil R.; Rocheleau, Ghislain; Roden, M. W.; Sampson, Michael J.; Meitinger, Thomas; Shields, Beverley M.; Shrader, Peter J.; Sigurdsson, Gunnar Th; Spars Thomas H.; Strassburger, Klaus; Stringham, Heather M.; Sun, Qi; Swift, Amy J.; Thorand, Barbara; Tichet, Jean; Tuomi, Tiinamaija; van Dam, Robertus Martinus; van Haeften, Timon W.; van Herpt, Thijs T.W.; van Vliet-Ostaptchouk, Jana V.; Walters, G. Bragi; Weedon, Michael N.; Wijmenga, Cisca; Witteman, Jacqueline C.M.; Bergman, Richard N.; Cauchi, Sthane S.; Collins, Francis S.; Gloyn, Anna L.; Gyllensten, Ulf B.; Hansen, Torben Skovbo; Hide, Winston A.; Hitman, Graham A.; Hofman, Albert; Hunter, D. J.; Hveem, Kristian; Laakso, M. M.; Mohlke, Karen L.; Morris, Andrew D.; Palmer, Colin Neil Alexander; Pramstaller, Peter P.; Rudan, Igor; Sijbrands, Eric J.G.; Stein, Lincoln D.; Tuomilehto, Jaakko O.I.; Uitterlinden, AndrG.; Walker, Mark A.; Wareham, Nicholas J.; Watanabe, Richard M.; Abecasis, Gonlo R.; Bhm, Bernhard Otto; Campbell, Harry; Daly, Mark J.; Hattersley, Andrew T.; Hu, Frank B.; Meigs, James B.; Pankow, Jim S.; Pedersen, Oluf Borbye; Wichmann, Heinz Erich; Barroso, In E.; Florez, Jose C.; Frayling, Tim M.; Groop, Leif C.; Sladek, Robert S.; Thorsteinsdtir, Unnur Arna; Wilson, James F.; Illig, Thomas; Froguel, Philippe; van Duijn, Cornelia M.; Stefsson, Kari; Altshuler, David M.; Boehnke, Michael L.; McCarthy, Mark I.; Soranzo, Nicole; Wheeler, Eleanor; Glazer, Nicole L.; Bouatia-Naji, Nabila; Mi, Reedik; Randall, Joshua C.; Johnson, Toby; Elliott, Paul; Rybin, Denis V.; Thorleifsson, Gudmar; Henneman, Peter; Dehghan, Abbas; Hottenga, Jouke Jan; Song, Kjioung S.; Goel, Anuj; Egan, Josephine M.; Lajunen, Taina K.; Doney, Alexander S.F.; Kanoni, Stavroula; Cavalcanti-Proen, Christine; Kumari, Meena; Timpson, Nicholas J.; Zabena, Carina A.; Ingelsson, Erik; An, Ping; OConnell, Jeffrey R.; Luan, Jian'fan A.; Roccasecca, Rosa Maria; Pattou, Franis N.; Sethupathy, Praveen; Ariyek, Yavuz; Barter, Philip J.; Beilby, John P.; Ben-Shlomo, Yoav; Bergmann, Sven Michael; Bochud, Murielle; Bonnefond, Amie; Borch-Johnsen, Knut; Btcher, Yvonne; Brunner, Eric John; Chen, Yii Der Ida; Clarke, Robert Joseph; Coin, Lachlan J.M.; Cooper, Matthew N.; Crisponi, Laura; Day, Ian N.M.; de Geus, Eco J.C.N.; Delplanque, Je; Fedson, Annette C.; Fischer-Rosinsk Antje; Forouhi, Nita G.; Frants, Rune R.; Franzosi, Maria Grazia; Gal, Pilar; Ogoodarzi, Mark; Graessler, Juergen; Grundy, Scott M.; Gwilliam, Rhian; Hallmans, Goran; Hammond, Naomi; Han, Xijing; Hartikainen, Anna Liisa; Hayward, Caroline; Heath, Simon C.; Hercberg, Serge; Hicks, Andrew Anthony; Hillman, David R.; Hingorani, Aroon Dinesh; Hui, Jennie; Hung, Joseph C.; Jula, Antti M.; Kaakinen, Marika A.; Kaprio, Jaakko A.; Kesaniemi, YrjAntero; Kivimaki, Mika Shipley; Knight, Bridget Ann; Koskinen, Seppo VnPellervo; Kovs, Per F.; Kyvik, Kirsten Ohm; Lathrop, Mark G.; Lawlor, Debbie A.; Bacquer, Olivier Le; Lecoeur, Cile; Li, Yun; Mahley, Robert W.; Mangino, Massimo; Manning, Alisa Knodle; Martez-Larrad, Mar Teresa; McAteer, Jarred B.; McPherson, Ruth; Meisinger, Christa; Melzer, David; Meyre, David; Mitchell, Braxton D.; Mukherjee, Sutapa A.; Naitza, Silvia; Neville, Matt J.; Oostra, Ben A.; Orru, Marco; Pakyz, Ruth E.; Paolisso, Giuseppe; Pattaro, Cristian; Pearson, Daniel S.; Peden, John F.; Pedersen, Nancy Lee; Perola, Markus; Pfeiffer, Andreas F.H.; Pichler, Irene; Polaek, Ozren; Posthuma, Danile; Potter, Simon C.; Pouta, Anneli M.; Province, Michael A.; Psaty, Bruce M.; Rice, Kenneth Martin; Ripatti, Samuli; Rivadeneira, Fernando R.; Rolandsson, Olov; Sandb, Annelli; Sandhu, Manjinder Singh; Sanna, Serena; Sayer, A. A.; Scheet, Paul A.; Seedorf, Udo; Sharp, Stephen John; Silveira, Angela Maria Vidigal; Simpson, Laila; Singleton, Andrew B.; Smith, Nicholas L.; Sovio, Ulla; Syddall, Holly Emma; Syven, Ann Christine; Tanaka, Toshiko; Tjes, Anke; van Dijk, Ko Willems; Varma, Dhiraj; Visvikis-Siest, Sophie; Vitart, Vonique; Vogelzangs, Nicole; Waeber, Gard; Wagner, Peter J.; Walley, Andrew John; Ward, Kim L.; Watkins, Hugh C.; Wild, Sarah H.; Willemsen, Gonneke A.H.M.; Yarnell, John W.G.; Zika, Diana; Zethelius, Bjn; Zhai, Guangju; Zhao, Jinghua; Zillikens, Maria Carola; Borecki, Ingrid B.; Loos, Ruth J.f.; Meneton, Pierre; Magnusson, Patrik K.E.; Nathan, David Matthew; Williams, Gordon H.; Silander, Kaisa; Salomaa, Veikko V.; Davey Smith, George; Bornstein, Stefan R.; Schwarz, Peter Ee H.; Spranger, Joachim; Karpe, Fredrik; Shuldiner, Alan R.; Cooper, Cyrus C.; Dedoussis, George V.Z.; Serrano-Rs, Manuel; Dmorris, Andrew; Lind, Lars L.; Palmer, Lyle J.; Hul, Frank B.; Franks, Paul W.; Ebrahim, Shah B.; Marmot, M. G.; Wright, Alan F.; Stumvoll, Michael W.; Buchanan, Thomas A.; Valle, Timo T.; Rotter, Jerome I.; Siscovick, David S.; Penninx, Brenda W. J. H.; Boomsma, Dorret I.; Deloukas, Panos; Spector, Tim David; Ferrucci, Luigi G.; Cao, Antonio; Scuteri, Angelo; Schlessinger, David; Uda, Manuela; Ruokonen, Aimo O.; J?arvelin, Mjo Riitta R.; Waterworth, Dawn M.; Vollenweider, Peter K.; Peltonen-Palotie, Leena Johanna; Mooser, Vincent E.
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Morgan, Philip E.; Pattison, David I.; Davies, Michael J.Proteins are a major target for oxidation due to their abundance and high reactivity. Despite extensive investigation over many years, only limited quantitative data exist on the contributions of different pathways to the oxidation of peptides and proteins. This study was designed to obtain quantitative data on the nature and yields of oxidation products (alcohols, carbonyls, hydroperoxides, fragment species) formed by a prototypic oxidant system (HO /O <inf>2</inf>) on small peptides of limited, but known, amino acid composition. Peptides composed of Gly, Ala, Val, and Pro were examined with particular emphasis on the peptide Val-Gly-Val-Ala-Pro-Gly, a repeat motif in elastin with chemotactic activity and metalloproteinase regulation properties. The data obtained indicate that hydroperoxide formation occurs nonrandomly (Pro > Val > Ala > Gly) with this inversely related to carbonyl yields (both peptide-bound and released). Multiple alcohols are generated at both side-chain and backbone sites. Backbone fragmentation has been characterized at multiple positions, with sites adjacent to Pro residues being of major importance. Summation of the product concentrations provides clear evidence for the occurrence of chain reactions in peptides exposed to HO /O <inf>2</inf>, with the overall product yields exceeding that of the initial HO generated. 2011 Elsevier Inc.
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Loh, Kim; Merry, Troy L.; Gali?, Sandra; Wu, Ben Jing; Watt, Matthew J.; Zhang, Sheng; Zhang, Zhongtao Yin; Neel, Benjamin G.; Tiganis, TonyAims/hypothesis: Insulin activates insulin receptor protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The insulin receptor can serve as a substrate for the protein tyrosine phosphatase (PTP) 1B and T cell protein tyrosine phosphatase (TCPTP), which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the insulin receptor in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates insulin receptor signalling and gluconeogenesis in the liver. In this study we assessed for the first time the role of TCPTP in the regulation of insulin receptor signalling in muscle. Methods: We generated muscle-specific TCPTP-deficient (Mck-Cre;Ptpn2 lox/lox ) mice (Mck, also known as Ckm) and assessed the impact on glucose homeostasis and muscle insulin receptor signalling in chow-fed versus high-fat-fed mice. Results: Blood glucose and insulin levels, insulin and glucose tolerance, and insulin-induced muscle insulin receptor activation and downstream PI3K/Akt signalling remained unaltered in chow-fed Mck-Cre;Ptpn2 lox/lox versus Ptpn2 lox/lox mice. In addition, body weight, adiposity, energy expenditure, insulin sensitivity and glucose homeostasis were not altered in high-fat-fed Mck-Cre;Ptpn2 lox/lox versus Ptpn2 lox/lox mice. Conclusions/interpretation: These results indicate that TCPTP deficiency in muscle has no effect on insulin signalling and glucose homeostasis, and does not prevent high-fat diet-induced insulin resistance. Thus, despite their high degree of sequence identity, PTP1B and TCPTP contribute differentially to insulin receptor regulation in muscle. Our results are consistent with the notion that these two highly related PTPs make distinct contributions to insulin receptor regulation in different tissues. 2011 Springer-Verlag.
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Arsenault, Beno J.; Boekholdt, S. M.; Hovingh, Gerard Kees; Hyde, Craig L.; DeMicco, David A.; Chatterjee, Aurobindo; Barter, Philip J.; Deedwania, Prakash ?.; Waters, David D.; LaRosa, John C.; Pedersen, Terje R.; Kastelein, Johannes Jacob PieterBackground-Carriers of the KIF6 719Arg variant may be at increased risk for CVD and may benefit more from statin therapy, in terms of CVD risk reduction, than noncarriers. Our objective was to investigate whether carriers of the KIF6 719Arg genetic variant (rs20455) are at increased cardiovascular risk and obtain more benefit from high-dose statin therapy than do noncarriers. Methods and Results-We used an adjusted Cox proportional hazard model to assess the hazard ratio (HR) for the reduction of major cardiovascular events by 80 mg/d atorvastatin over 10 mg/d atorvastatin in 4599 patients of the Treating to New Targets (TNT) study and by 80 mg/d atorvastatin over 20-40 mg/d simvastatin in 6541 patients of the Incremental Decrease in End Points Through Aggressive Lipid-Lowering (IDEAL) study. A total of 381 and 648 patients had a cardiovascular event during follow-up in TNT and IDEAL, respectively. Heterozygotes and homozygotes for the minor allele were not at increased risk compared with noncarriers. In TNT, for noncarriers of the 719Arg allele, the HR for high- versus low-dose atorvastatin was 0.81 (95% confidence interval, 0.59 -1.11). In carriers of 1 or 2 minor alleles, the HR was 0.85 (0.66 -1.11) and carriers of 2 copies of the minor allele obtained a significant risk reduction (HR: 0.44, 95% confidence interval, 0.23- 0.84). In IDEAL, the respective HRs were 0.85 (0.67-1.10), 0.88 (0.62-1.07) and 0.91 (0.58 -1.43). The interaction term for carrier status by treatment was also nonsignificant (P<0.810 in TNT and P=0.909 in IDEAL). Conclusions-In these 2 large, randomized clinical trials, carriers of the KIF6 719Arg allele were not at increased cardiovascular risk and did not obtain consistent cardiovascular benefit from high-dose statin therapy compared with noncarriers. 2011 American Heart Association, Inc.
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Barrett, Tessa J.; Hawkins, Clare L.Hypothiocyanous acid (HOSCN) is produced in biological systems by the peroxidase-catalyzed reaction of thiocyanate (SCN -) with H <inf>2</inf>O <inf>2</inf>. This oxidant plays an important role in the human immune system, owing to its potent bacteriostatic properties. Significant amounts of HOSCN are also formed by immune cells under inflammatory conditions, yet the reactivity of this oxidant with host tissue is poorly characterized. Traditionally, HOSCN has been viewed as a mild oxidant, which is innocuous to mammalian cells. Indeed, recent studies show that the presence of SCN in airways has a protective (Figure presented) function, by preventing the formation of other, more damaging, inflammatory oxidants. However, there is an increasing body of evidence that challenges this dogma, showing that the selectivity of HOSCN for specific thiol-containing cellular targets results in the initiation of significant cellular damage. This propensity to induce cellular dysfunction is gaining considerable interest, particularly in the cardiovascular field, as smokers have elevated plasma SCN -, the precursor for HOSCN. his review will outline the beneficial and detrimental aspects of HOSCN formation in biological systems. 2011 American Chemical Society.
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Midwinter, Robyn G.; Maghzal, Ghassan J.; Dennis, Joanne Marie; Wu, Ben Jing; Cai, Hong; Kapralov, A. A.; Belikova, Natalia A.; Tyurina, Yulia Yu; Dong, Lanfeng; Khachigian, Levon M.; Neuil, Ji? Kagan, Valerian E.; Stocker, RolandProbucol inhibits the proliferation of vascular smooth muscle cells in vitro and in vivo, and the drug reduces intimal hyperplasia and atherosclerosis in animals via induction of heme oxygenase-1 (HO-1). Because the succinyl ester of probucol, succinobucol, recently failed as an antiatherogenic drug in humans, we investigated its effects on smooth muscle cell proliferation. Succinobucol and probucol induced HO-1 and decreased cell proliferation in rat aortic smooth muscle cells. However, whereas inhibition of HO-1 reversed the antiproliferative effects of probucol, this was not observed with succinobucol. Instead, succinobucol but not probucol induced caspase activity and apoptosis, and it increased mitochondrial oxidation of hydroethidine to ethidium, suggestive of the participation of H <inf>2</inf>O <inf>2</inf> and cytochrome c. Also, succinobucol but not probucol converted cytochrome c into a peroxidase in the presence of H <inf>2</inf>O <inf>2</inf>, and succinobucol-induced apoptosis was decreased in cells that lacked cytochrome c or a functional mitochondrial complex II. In addition, succinobucol increased apoptosis of vascular smooth muscle cells in vivo after balloon angioplasty-mediated vascular injury. Our results suggest that succinobucol induces apoptosis via a pathway involving mitochondrial complex II, H <inf>2</inf>O <inf>2</inf>, and cytochrome c. These unexpected results are discussed in light of the failure of succinobucol as an antiatherogenic drug in humans. 2011 Elsevier Inc. All rights reserved.
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Nicholls, Stephen J.; Gordon, Allan; Johannson, Jan; Ballantyne, Christie Mitchell; Barter, Philip J.; Brewer, Hollis Bryan; Kastelein, Johannes Jacob Pieter; Wong, Norman C.W.; Borgman, Marilyn R.N.; Nissen, Steven E.Background Considerable interest has focused on the development of therapies that target the functionality of high-density lipoproteins (HDL). Upregulation of endogenous synthesis of the major protein on HDL particles, apolipoprotein A-I (apoAI), represents a novel approach to generation of new HDL particles. The Study of Quantitative Serial Trends in Lipids with Apolipoprotein A-I Stimulation (SUSTAIN, NCT01423188) study aims to evaluate the lipid efficacy, safety and tolerability of an apoA-I inducer (RVX-208). The ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE, NCT01067820) study aims to evaluate the effect of RVX-208 on plaque burden. Methods In SUSTAIN, 172 patients with low levels of HDL-C will be randomized to receive RVX-208 100 mg bid or placebo for 24 weeks. The primary efficacy parameter will be the percentage change in HDL-C levels. In ASSURE, 310 patients with angiographic coronary artery disease and low HDL-C levels will be randomized to receive RVX-208 100 mg bid or placebo for 26 weeks. The primary efficacy parameter will be the nominal change in percent atheroma volume (PAV), determined by analysis of intravascular ultrasound (IVUS) images of matched coronary artery segments acquired at baseline and at 26-week follow-up. The effect of RVX-208 on other lipid and inflammatory markers, safety and tolerability will also be assessed in both studies. Conclusion ApoA-I induction represents a potential novel strategy to reduce cardiovascular risk, by generating nascent HDL particles. These studies will provide early evaluation of the effects of RVX-208 on lipids and atherosclerotic plaque. 2012 Springer Science+Business Media, LLC.
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Ernst, Edzard Edzard W.; Snyder, John; Dunlop, Rachael AnneThe work of the National Center for Complementary and Alternative Medicine (NCCAM) has repeatedly been criticised. Much of this criticism relates to the past funding of studies of acupuncture. The aim of this article is to provide an independent, critical evaluation of the data produced by NCCAM-funded RCTs of acupuncture. Relevant studies were identified using PubMed. Studies were included if they were NCCAM-funded RCTs of acupuncture. Excluded were secondary reports of primary studies, RCTs not testing the effectiveness of acupuncture and National Institutes of Health-funded studies not mentioning NCCAM support. One author extracted the data according to predefined criteria and assessed the risk of bias. The other authors verified these tasks. Thirteen RCTs were included, with sample sizes ranging from seven to 570. Most studies reported pain as the primary outcome. Six RCTs suggested acupuncture was effective. Seven RCTs had a low risk of bias. Numerous methodological shortcomings were identified. Many NCCAM-funded RCTs of acupuncture have important limitations. These findings might improve future studies of acupuncture and could be considered in the ongoing debate regarding NCCAM-funding. 2011 The Authors. FACT 2011. Royal Pharmaceutical Society.
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Li, Xiaohong; McGrath, Kristine C.Y.; Nammi, Srinivas; Heather, Alison Kay; Roufogalis, Basil D.The aim of this study was to investigate whether treatment with a ginger (Zingiber officinale) extract of high-fat diet (HFD)-fed rats suppresses Nuclear factor-kappa B (NF-?B)-driven hepatic inflammation and to subsequently explore the molecular mechanisms in vitro. Adult male Sprague-Dawley rats were treated with an ethanolic extract of Zingiber officinale (400mg/kg) along with a HFD for 6weeks. Hepatic cytokine mRNA levels, cytokine protein levels and NF-?B activation were measured by real-time PCR, Western blot and an NF-?B nuclear translocation assay, respectively. In vitro, cell culture studies were carried out in human hepatocyte (HuH-7) cells by treatment with Zingiber officinale (100?g/mL) for 24hr prior to interleukin-1? (IL-1?, 8ng/mL)-induced inflammation. We showed that Zingiber officinale treatment decreased cytokine gene TNF? and IL-6 expression in HFD-fed rats, which was associated with suppression of NF-?B activation. In vitro, Zingiber officinale treatment decreased NF-?B-target inflammatory gene expression of IL-6, IL-8 and serum amyloid A1 (SAA1), while it suppressed NF-?B activity, I?B? degradation and I?B kinase (IKK) activity. In conclusion, Zingiber officinale suppressed markers of hepatic inflammation in HFD-fed rats, as demonstrated by decreased hepatic cytokine gene expression and decreased NF-?B activation. The study demonstrates that the anti-inflammatory effect of Zingiber officinale occurs at least in part through the NF-?B signalling pathway. 2011 The Authors. Basic and Clinical Pharmacology and Toxicology 2011 Nordic Pharmacological Society.
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Gao, Xia; Gu, Hongmei; Li, Ge; Rye, Kerry Anne; Zhang, DaweiThe ATP-binding cassette transporter G1 (ABCG1) mediates free cholesterol efflux onto lipidated apolipoprotein A-I (apoA-I) and plays an important role in macrophage reverse cholesterol transport thereby reducing atherosclerosis. However, how ABCG1 mediates the efflux of cholesterol onto lipidated apoA-I is unclear. Since the crystal structure of ABCG family is not available, other approaches such as site-directed mutagenesis have been widely used to identify amino acid residues important for protein functions. We noticed that ABCG1 contains a single cysteine residue in its putative transmembrane domains. This cysteine residue locates at position 514 (Cys514) within the third putative transmembrane domain and is highly conserved. Replacement of Cys 514 with Ala (C514A) essentially abolished ABCG1-mediated cholesterol efflux onto lipidated apoA-I. Substitution of Cys514 with more conserved amino acid residues, Ser or Thr, also significantly decreased cholesterol efflux. However, mutation C514A had no detectable effect on protein stability and trafficking. Mutation C514A also did not affect the dimerization of ABCG1. Our findings demonstrated that the sulfhydryl group of Cys residue located at position 514 plays a critical role in ABCG1-mediated cholesterol efflux. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). 2011 Elsevier B.V. All rights reserved.
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Rye, Kerry Anne; Barter, Philip J.The inverse relationship between plasma HDL levels and the risk of developing coronary heart disease is well established. The underlying mechanisms of this relationship are poorly understood, largely because HDL consist of several functionally distinct subpopulations of particles that are continuously being interconverted from one to another. This review commences with an outline of what is known about the origins of individual HDL subpopulations, how their distribution is regulated, and describes strategies that are currently available for isolating them. We then summarise what is known about the functionality of specific HDL subpopulations, and how these findings might impact on cardiovascular risk. The final section highlights major gaps in existing knowledge of HDL functionality, and suggests how these deficiencies might be addressed. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). 2011 Elsevier B.V. All rights reserved.
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Hooper, Lee; Kay, Colin D.; Abdelhamid, Asmaa S.; Kroon, Paul A.; Cohn, Jeffrey S.; Rimm, Eric B.; Cassidy, AedBackground: There is substantial interest in chocolate and flavan-3-ols for the prevention of cardiovascular disease (CVD). Objective: The objective was to systematically review the effects of chocolate, cocoa, and flavan-3-ols on major CVD risk factors. Design: We searched Medline, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) of chocolate, cocoa, or flavan-3-ols. We contacted authors for additional data and conducted duplicate assessment of study inclusion, data extraction, validity, and randomeffects meta-analyses. Results: We included 42 acute or short-term chronic (?18 wk) RCTs that comprised 1297 participants. Insulin resistance (HOMA-IR: -0.67; 95% CI: -0.98, -0.36) was improved by chocolate or cocoa due to significant reductions in serum insulin. Flow-mediated dilatation (FMD) improved after chronic (1.34%; 95% CI: 1.00%, 1.68%) and acute (3.19%; 95% CI: 2.04%, 4.33%) intakes. Effects on HOMAIR and FMD remained stable to sensitivity analyses. We observed reductions in diastolic blood pressure (BP; -1.60 mm Hg; 95% CI: -2.77, 20.43 mm Hg) and mean arterial pressure (-1.64 mm Hg; 95% CI: -3.27, -0.01 mm Hg) and marginally significant effects on LDL (-0.07 mmol/L; 95% CI: -0.13, 0.00 mmol/L) and HDL (0.03 mmol/L; 95% CI: 0.00, 0.06 mmol/L) cholesterol. Chocolate or cocoa improved FMD regardless of the dose consumed, whereas doses >50 mg epicatechin/d resulted in greater effects on systolic and diastolic BP. GRADE (Grading of Recommendations, Assessment, Development and Evaluation, a tool to assess quality of evidence and strength of recommendations) suggested low- to moderate-quality evidence of beneficial effects, with no suggestion of negative effects. The strength of evidence was lowered due to unclear reporting for allocation concealment, dropouts, missing data on outcomes, and heterogeneity in biomarker results in some studies. Conclusions: We found consistent acute and chronic benefits of chocolate or cocoa on FMD and previously unreported promising effects on insulin and HOMA-IR. Larger, longer-duration, and independently funded trials are required to confirm the potential cardiovascular benefits of cocoa flavan-3-ols. 2012 American Society for Nutrition.
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Barrett, Tessa J.; Pattison, David I.; Leonard, Stephen E.; Carroll, Kate S.; Davies, Michael J.; Hawkins, Clare L.Myeloperoxidase (MPO) forms reactive oxidants including hypochlorous and hypothiocyanous acids (HOCl and HOSCN) under inflammatory conditions. HOCl causes extensive tissue damage and plays a role in the progression of many inflammatory-based diseases. Although HOSCN is a major MPO oxidant, particularly in smokers, who have elevated plasma thiocyanate, the role of this oxidant in disease is poorly characterized. HOSCN induces cellular damage by targeting thiols. However, the specific targets and mechanisms involved in this process are not well defined. We show that exposure of macrophages to HOSCN results in the inactivation of intracellular enzymes, including creatine kinase (CK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In each case, the active-site thiol residue is particularly sensitive to oxidation, with evidence for reversible inactivation and the formation of sulfenyl thiocyanate and sulfenic acid intermediates, on treatment with HOSCN (less than fivefold molar excess). Experiments with DAz-2, a cell-permeable chemical trap for sulfenic acids, demonstrate that these intermediates are formed on many cellular proteins, including GAPDH and CK, in macrophages exposed to HOSCN. This is the first direct evidence for the formation of protein sulfenic acids in HOSCN-treated cells and highlights the potential of this oxidant to perturb redox signaling processes. 2012 Elsevier Inc. All rights reserved.
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Dastani, Zari; Hivert, Marie France; Timpson, Nicholas J.; Yuan, Xin; Lyytiknen, Leo Pekka; Tanaka, Toshiko; Morris, Andrew Paul; Isaacs, Aaron; Lohman, Kurt K.; Qi, Lu; Kanoni, Stavroula; Pankow, Jim S.; Grimsby, Jonna L.; Liu, Chingti; Mooser, Vincent E.; Chambers, John Campbell; Wareham, Nicholas J.; Langenberg, Claudia C.; Frants, Rune R.; Winkler, Thomas Wolfgang; Psaty, Bruce M.; Chen, Ida Yii Der; Viikari, Jorma S.A.; Ken, Mika A.P.; Pramstaller, Peter P.; Evans, David M.; St Pourcain, Beate; Wood, Andrew R.; Bandinelli, Stefania S.; Egan, Josephine M.; Bringer, Stefan; van Heemst, Diana; Nuotio, Marja Liisa; Garcia, Melissa E.; Haun, Margot; Deloukas, Panos; Couper, David J.; Florez, Jose C.; Magic Consortium; Wilson, James G.; Guo, Xiuqing; Johnson, Toby; Teslovich, Tanya M.; Meulenbelt, Ingrid M.; Dedoussis, George V.Z.; Hu, Frank B.; Liu, Yongmei; Paulweber, Bernhard; Spector, Tim David; Frayling, Tim M.; Davey Smith, George; Siscovick, David S.; Kronenberg, Florian; van Duijn, Cornelia M.; Waterworth, Dawn M.; Meigs, James B.; Richards, John Brent; Voight, Benjamin F.; Scott, Laura J.; Steinthsdtir, Valgerdur; Dina, Christian; Welch, Ryan P.; Zeggini, Eleftheria; Huth, Cornelia; Aulchenko, Yurii S.; Thorleifsson, Gudmar; McCulloch, Laura J.; Ferreira, Teresa; Raychaudhuri, Soumya; Bennett, Amanda J.; Blagieva, Roza; Boerwinkle, Eric A.; Bengtsson-Bostr, Kristina; Bumpstead, Suzannah J.; Burtt, Nl P.; Chines, Peter S.; Green, Todd; Groves, Christopher James; Guiducci, Candace; Hadjadj, Samy; Hassanali, Neelam; Isomaa, Bo A.; Jackson, Anne U.; Kong, Augustine S.; Li, Man; Lindgren, Cecilia M.; Marre, Michel; Meitinger, Thomas A.; Morken, Mario A.; Owen, Katharine R.; Payne, Felicity; Proen, Christine; Prokopenko, Inga I.; Roden, M. W.; Sampson, Michael J.; Meitinger, Thomas; Spars Thomas; Stringham, Heather M.; Thorand, Barbara; van Dam, Rob M.; Walters, G. Bragi; Weedon, Michael N.; Cauchi, Sthane S.; Hofman, Albert; Morris, Andrew D.; Sijbrands, Eric J.G.; Stein, Lincoln D.; Uitterlinden, AndrG.; Watanabe, Richard M.; Daly, Mark J.; Groop, Leif C.; Thorsteinsdtir, Unnur Arna; Altshuler, David M.; Mi, Reedik; Rybin, Denis V.; Goel, Anuj; Ingelsson, Erik; Luan, Jian'fan A.; Elliott, Amanda L.; Sethupathy, Praveen; Ariyek, Yavuz; Bergmann, Sven Michael; Bonnefond, Amie; Brunner, Eric John; Clarke, Robert Joseph; Coin, Lachlan J.M.; Day, Ian N.M.; de Geus, Eco J.C.N.; Delplanque, Je; Forouhi, Nita G.; Goodarzi, Mark O.; Gwilliam, Rhian; Hammond, Naomi; Hayward, Caroline; Heath, Simon C.; Hingorani, Aroon Dinesh; Hui, Jennie; Kivimaki, Mika Shipley; Koskinen, Seppo VnPellervo; Kyvik, Kirsten Ohm; Lawlor, Debbie A.; Li, Yun; Mangino, Massimo; Martez-Larrad, Mar Teresa; McAteer, Jarred B.; Meisinger, Christa; Meyre, David; Mitchell, Braxton D.; Naitza, Silvia; Neville, Matt J.; Pattaro, Cristian; Pearson, Daniel S.; Peden, John F.; Pichler, Irene; Potter, Simon C.; Ripatti, Samuli; Rivadeneira, Fernando R.; Rolandsson, Olov; Sandhu, Manjinder Singh; Scheet, Paul A.; Sharp, Stephen John; Sigurson, Gunnar; Silveira, Angela Maria Vidigal; Simpson, Laila; Sovio, Ulla; Swift, Amy J.; Varma, Dhiraj; Vitart, Vonique; Wagner, Peter J.; Watkins, Hugh C.; Willemsen, Gonneke A.H.M.; Zhao, Jinghua; Borecki, Ingrid B.; Magnusson, Patrik K.E.; Nathan, David Matthew; Williams, Gordon H.; Spranger, Joachim; Karpe, Fredrik; Serrano-Rs, Manuel; Palmer, Lyle J.; Wright, Alan F.; Stumvoll, Michael W.; Rotter, Jerome I.; Boomsma, Dorret I.; Cao, Antonio; Scuteri, Angelo; Schlessinger, David; Ruokonen, Aimo O.; J?arvelin, Mjo Riitta R.; Peltonen-Palotie, Leena Johanna; Musunuru, Kiran; O'Donnell, Christopher J.; Pirruccello, James P.; Peloso, Gina Marie; Ricketts, Sally L.; Li, Xiaohui; Lee, Jong-young; Kim, Kyunga Ha; Smith, Josh D.; Zee, Robert Y.L.; Whitfield, John B.; Surakka, Ida L.; Sinisalo, Juha P.; Saharinen, Juha; Rose, Lynda M.; Rieder, Mark J.; Parker, Alex N.; O?Donnell, Christopher J.; Masson, David; Martin, Nicholas G.; Marroni, Fabio; Luben, Robert N.; Lokki, Marja Liisa L.; Lettre, Guillaume; Lakatta, Edward G.; Kig, Inke Regina; Khaw, Kay Tee T.; Kaplan, Lee M.; Janssens, A. Cile Jw W.; Hovingh, Gerard Kees Kornelis; Hastie, Nicholas Dixon; Gonzalez, Elena; Luben, Robert N.; Erdmann, Jeanette; Ejebe, Kenechi G.; Demissie, Serkalem; Boekholdt, S. M.; Seielstad, Mark; Wong, Tienyin; Gabriel, Stacey Bolk; Gudhason, Vilmundur; Reilly, Muredach P.; Schunkert, Heribert; Cupples, Laura Adrienne
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Omega-3 supplementation and non-alcoholic fatty liver disease: A systematic review and meta-analysisParker, Helen M.; Johnson, Nathan A.; Burdon, Catriona A.; Cohn, Jeffrey S.; O'Connor, Helen T.; George, Jacob A.Non-alcoholic fatty liver disease (NAFLD) is a frequent accompaniment of obesity and insulin resistance. With the prevalence approaching 85% in obese populations, new therapeutic approaches to manage NAFLD are warranted. A systematic search of the literature was conducted for studies pertaining to the effect of omega-3 polyunsaturated fatty acid (PUFA) supplementation on NAFLD in humans. Primary outcome measures were liver fat and liver function tests: alanine aminotransferase (ALT) and aspartate aminotransferase [1]. Data were pooled and meta-analyses conducted using a random effects model. Nine eligible studies, involving 355 individuals given either omega-3 PUFA or control treatment were included. Beneficial changes in liver fat favoured PUFA treatment (effect size = -0.97, 95% CI: -0.58 to -1.35, p <0.001). A benefit of PUFA vs. control was also observed for AST (effect size = -0.97, 95% CI: -0.13 to -1.82, p = 0.02). There was a trend towards favouring PUFA treatment on ALT but this was not significant (effect size = -0.56, 95% CI: -1.16 to 0.03, p = 0.06). Sub-analyses of only randomised control trials (RCTs) showed a significant benefit for PUFA vs. control on liver fat (effect size = -0.96, 95% CI: -0.43 to -1.48, p <0.001), but not for ALT (p = 0.74) or AST (p = 0.28). There was significant heterogeneity between studies. The pooled data suggest that omega-3 PUFA supplementation may decrease liver fat, however, the optimal dose is currently not known. Well designed RCTs which quantify the magnitude of effect of omega-3 PUFA supplementation on liver fat are needed. 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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Drew, Brian G.; Rye, Kerry Anne; Duffy, Stephen James; Barter, Philip J.; Kingwell, BronwynA low plasma level of HDL cholesterol is an atherosclerotic risk factor; however, emerging evidence suggests that low HDL levels might also contribute to the pathophysiology of type 2 diabetes mellitus (T2DM) through direct effects on plasma glucose. In the past decade, animal and clinical studies have uncovered a previously undescribed spectrum of HDL actions, indicating that HDL may control glucose homeostasis through mechanisms including insulin secretion, direct glucose uptake by muscle via the AMP-activated protein kinase, and possibly enhanced insulin sensitivity. These effects are mediated by multiple cell types via mechanisms including preservation of cell function through cellular lipid removal and also via direct signaling events. We suggest a paradigm shift from HDL being a bystander to being an active player in diabetic pathophysiology, which raises the possibility that HDL elevation could be a novel therapeutic avenue for T2DM. The entry of HDL-raising agents of the cholesteryl ester transfer protein (CETP) inhibitor class into late-phase clinical trials creates potential for rapid clinical translation. This Review will discuss the emerging evidence for a role of HDL-mediated glucose regulation in the pathophysiology of T2DM, and will also outline the therapeutic potential for HDL elevation for the prevention and management of T2DM. 2012 Macmillan Publishers Limited. All rights reserved.
