Publications

Showing 1081–1100 of 2058 publications.

• High-density lipoproteins inhibit vascular endothelial inflammation by increasing 3?-hydroxysteroid-[INCREMENT]24 reductase expression and inducing heme oxygenase-1
  Wu, Ben Jing; Chen, Kang; Shrestha, Sudichhya; Ong, Kwok Leung; Barter, Philip J.; Rye, Kerry Anne
  Circulation Research (Vol. 112/2) – 2013
  Rationale: Lipid-free apolipoprotein (apo) A-I and discoidal reconstituted high-density lipoproteins (rHDL) containing apoA-I, (A-I)rHDL, inhibit vascular inflammation by increasing 3?-hydroxysteroid-[INCREMENT]24 reductase (DHCR24) expression. Objective: To determine whether the lipid-free apoA-I-mediated and (A-I)rHDL-mediated increase in DHCR24 expression induces the cytoprotective and potentially cardioprotective enzyme, heme oxygenase-1 (HO-1). Methods and Results: In vivo: A single intravenous infusion of lipid-free apoA-I (8 mg/kg) administered 24 hours before inserting a nonocclusive periarterial carotid collar into New Zealand White rabbits decreased collar-induced endothelial vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression, reduced intima/media neutrophil infiltration, and increased DHCR24 and HO-1 mRNA levels. Knockdown of vascular DHCR24 and HO-1 and systemic administration of tin-protoporphyrin-IX, an HO inhibitor, abolished these anti-inflammatory effects. In vitro: Preincubation of human coronary artery endothelial cells with (A-I)rHDL before activation with tumor necrosis factor-? increased DHCR24 and HO-1 mRNA levels and inhibited cytokine-induced vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression. Transfection of the cells with DHCR24 and HO-1 small interfering RNA and tin-protoporphyrin-IX treatment abolished these effects. The (A-I)rHDL-mediated induction of HO-1 was reduced in human coronary artery endothelial cells transfected with DHCR24 small interfering RNA. Transfection of human coronary artery endothelial cells with HO-1 small interfering RNA and tin-protoporphyrin-IX treatment did not inhibit the (A-I)rHDL-mediated increase in DHCR24 expression. Inhibition of phosphatidylinositol 3-kinase/Akt reduced the (A-I)rHDL-mediated increase in HO-1, but not DHCR24 expression. The activation of phosphatidylinositol 3-kinase/Akt by (A-I)rHDL was decreased in human coronary artery endothelial cells that were transfected with DHCR24 small interfering RNA. Conclusions: Lipid-free apoA-I and (A-I)rHDL inhibit inflammation by increasing DHCR24 expression, which, in turn, activates phosphatidylinositol 3-kinase/Akt and induces HO-1. 2012 American Heart Association, Inc.
• Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study
  Chan, Kim Hoe; O'Connell, Rachel L.; Sullivan, David R.; Hoffmann, L. S.; Rajamani, Kushwin; Whiting, Malcolm J.; Donoghoe, Mark W.; Vanhala, Mauno J.; Hamer, Andrew W.; Yu, Bing; Stocker, Roland; Ng, Martin K.C.; Keech, Anthony C.
  Diabetologia (Vol. 56/4) – 2013
  Aims/hypothesis: Bilirubin has antioxidant and anti-inflammatory activities. Previous studies demonstrated that higher bilirubin levels were associated with reduced prevalence of peripheral arterial disease (PAD). However, the relationship between bilirubin and lower-limb amputation, a consequence of PAD, is currently unknown. We hypothesised that, in patients with type 2 diabetes, bilirubin concentrations may inversely associate with lower-limb amputation. Methods: The relationship between baseline plasma total bilirubin levels and amputation events was analysed in 9,795 type 2 diabetic patients from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. The analysis plan was pre-specified. Lower-limb amputation was adjudicated blinded to treatment allocation. Relevant clinical and biochemical data were available for analyses. Amputation was a pre-specified tertiary endpoint. Results: Bilirubin concentrations were significantly inversely associated with lower-limb amputation, with a greater than threefold risk gradient across levels. Individuals with lower bilirubin concentrations had a higher risk for first amputation (HR 1.38 per 5 ?mol/l decrease in bilirubin concentration, 95% CI 1.07, 1.79, p = 0.013). The same association persisted after adjustment for baseline variables, including age, height, smoking status, ?-glutamyltransferase level, HbA<inf>1c</inf>, trial treatment allocation (placebo vs fenofibrate), as well as previous PAD, non-PAD cardiovascular disease, amputation or diabetic skin ulcer, neuropathy, nephropathy and diabetic retinopathy (HR 1.38 per 5 ?mol/l decrease in bilirubin concentration, 95% CI 1.05, 1.81, p = 0.019). Conclusions/interpretation: Our results identify a significant inverse relationship between bilirubin levels and total lower-limb amputation, driven by major amputation. Our data raise the hypothesis that bilirubin may protect against amputation in type 2 diabetes. 2013 Springer-Verlag Berlin Heidelberg.
• Targeting the AGE-RAGE axis improves renal function in the context of a healthy diet low in advanced glycation end-product content
  Thallas-Bonke, Vicki; Coughlan, Melinda T.; Tan, Adeline L.Y.; Harcourt, Brooke E.; Morgan, Philip E.; Davies, Michael J.; Bach, Leon A.; Cooper, Mark Emmanuel; Forbes, Josephine Maree
  Nephrology (Vol. 18/1) – 2013
  Aim: Mouse chow is commonly high in advanced glycation end-products, known contributors to diabetic nephropathy. The aim of this study was to evaluate if targeting of the AGE-RAGE axis was still effective in the context of a diet low in AGE content, which is more comparable to diets consumed by individuals with type 1 diabetes. Methods: C57BL/6J wild-type and mice deficient in the receptor for AGEs (RAGE-KO) consumed a diet low in AGE content. Groups of mice were given (i) vehicle; (ii) streptozotocin; or (iii) streptozotocin + AGE lowering therapy (alagebrium chloride) and followed for 24 weeks. Results: Diabetic mice had high urinary albumin excretion rates, hyperfiltration and release of urinary Kim-1, not seen in diabetic RAGE-KO mice. Diabetic mice also had renal fibrosis, measured by glomerulosclerosis, tubulointerstitial expansion, TGF-?1 and glomerular collagen-IV deposition which almost all improved by RAGE-KO or alagebium. Diabetic mice had a greater renal burden of AGEs and increased expression of renal specific PKC-? phosphorylation, which was improved in RAGE-KO mice, or those treated with alagebrium. Conclusion: Diabetic mice given a low-AGE diet still developed renal disease, which could be attenuated by targeting of the AGE-RAGE axis. 2012 Asian Pacific Society of Nephrology.
• Assessment of cardiometabolic risk and prevalence of meeting treatment guidelines among patients with type 2 diabetes stratified according to their use of insulin and/or other diabetic medications: Results from INSPIRE ME IAA
  Smith, Jessica D.; Nazare, Julie Anne; Borel, Anne Laure; Aschner, Pablo J.; Barter, Philip J.; van Gaal, Luc F.; Matsuzawa, Ynji; Kadowaki, Takahashi; Ross, Robert; Brulle-Wohlhueter, Claire; Almas, Natalie; Haffner, Steven M.; Balkau, Beverley J.; Despr, Jean Pire
  Diabetes, Obesity and Metabolism (Vol. 15/7) – 2013
  Aim: Visceral adipose tissue (VAT) and liver fat (LF) are strongly associated with type 2 diabetes. It is not known, however, how diabetes treatment and/or risk factor management modulates the association between VAT, LF and diabetes. The aim was to determine the level of VAT and LF in patients with type 2 diabetes according to their treatment status and achievement of the American Diabetes Association's (ADA) diabetes management goals. Methods: We performed a cross-sectional analysis of the baseline data of the International Study of the Prediction of Intra-Abdominal Adiposity and its Relationship with Cardiometabolic risk/Intra-Abdominal Adiposity (INSPIRE ME IAA), a 3-year prospective cardiometabolic imaging study conducted in 29 countries. Patients (n=3991) were divided into four groups: (i) those without type 2 diabetes (noT2D n=1003 men, n=1027 women); (ii) those with type 2 diabetes but not treated with diabetes medications (T2Dnomeds n=248 men, n=198 women); (iii) those with type 2 diabetes and treated with diabetes medications but not yet using insulin (T2Dmeds-ins n=591 men, n=484 women) and (iv) those with type 2 diabetes and treated with insulin (T2Dmeds+ins n=233 men, n=207 women). Abdominal and liver adiposity were measured by computed tomography. Results: Fewer patients with high VAT or LF achieved the ADA's goals for high-density lipoprotein cholesterol (HDL-C) or triglycerides compared to patients with low VAT or LF. Visceral adiposity (p=0.02 men, p=0.003 women) and LF (p=0.0002 men, p=0.0004 women) increased among patients who met fewer of the ADA treatment criteria, regardless of type 2 diabetes treatment. Conclusion: Residual cardiometabolic risk exists among patients with type 2 diabetes characterized by elevated VAT and LF. 2013 Blackwell Publishing Ltd.
• A common biological basis of obesity and nicotine addiction
  Thorgeirsson, Thorgeir El; Gudbjartsson, Danl Fannar; Sulem, Patrick; Besenbacher, Sen; Styrksdtir, Unnur; Thorleifsson, Gudmar; Walters, G. Bragi; Furberg, H.; Sullivan, Patrick F.; Marchini, Jonathan L.; McCarthy, Mark I.; Steinthsdtir, Valgerdur; Thorsteinsdottir, Unnur; Stefsson, Ki; Surakka, Ida L.; Vink, Jacqueline M.; Amin, Najaf A.; Geller, Frank; Rafnar, Thunn; Esko, Tu; Walter, Stefan; Gieger, Christian; Rawal, Rajesh; Mangino, Massimo; Prokopenko, Inga I.; Mi, Reedik; Keskitalo, Kaisu; Gudjonsdottir, Iris H.; Grarsdtir, Sveig; Stansson, Hreinn; Aulchenko, Yurii S.; Nelis, Mari; Aben, Katja K.H.; Den Heijer, Martin; Soranzo, Nicole; Valdes, Ana M.; Steves, Claire J.; Uitterlinden, AndrG.; Hofman, Albert; Tjes, Anke; Kovs, Per F.; Hottenga, Jouke Jan; Willemsen, Gonneke A.H.M.; Vogelzangs, Nicole; Ding, Angela; Dahmen, Norbert; Nitz, Barbara; Ripatti, Samuli; Perola, Markus; Kettunen, Johannes; Hartikainen -, Anna Liisa; Pouta, Anneli; Laitinen, Jaana H.; Isohanni, Matti K.; Huei-Yi, Shen; Allen, Maxine; Krestyaninova, Maria A.; Hall, Alistair Scott; Thompson, John R.; karsson, Hni; Tyrfingsson, Thorarinn; Kiemeney, Lambertus A.L.M.; J?arvelin, Mjo Riitta R.; Salomaa, Veikko V.; Stumvoll, Michael W.; Spector, Tim David; Wichmann, Heinz-Erich Erich; Metspalu, Andres H.; Samani, Nilesh J.; Penninx, Brenda W. J. H.; Oostra, Ben A.; Boomsma, Dorret I.; Tiemeier, H. W.; van Duijn, Cornelia M.; Kaprio, Jaakko A.; Gulcher, Jeffrey Robert; Kim, Yunjung; Dackor, Jennifer; Boerwinkle, Eric A.; Franceschini, Nora; Ardissino, Diego; Bernardinelli, Luisa; Mannucci, Piermannuccio Mannuccio M.; Mauri, Francesco; Merlini, Piera Angelica; Absher, Devin Michael; Assimes, Themistocles L.; Fortmann, Stephen P.; Iribarren, Carlos; Knowles, Joshua W.; Assimes, Themistocles L.; Ferrucci, Luigi G.; Tanaka, Toshiko; Bis, Joshua C.M.; Furberg, Curt D.; Haritunians, Talin; McKnight, Barbara; Psaty, Bruce M.; Taylor, Kent D.; Thacker, Evan L.; Almgren, Peter; Groop, Leif C.; Ladenvall, Claes; Boehnke, Michael L.; Jackson, Anne U.; Mohlke, Karen L.; Stringham, Heather M.; Tuomilehto, Jaakko O.I.; Benjamin, Emelia J.; Hwang, Shihjen; Levy, Daniel A.; Preis, Sarah Rosner; Ramachandran, Vasan S.; Duan, Jubao; Gejman, Pablo V.; Levinson, Douglas F.; Sanders, Alan R.; Shi, Jianxin; Lips, Esther H.; McKay, James D.; Agudo, A. T.; Barzan, Luigi; Bencko, Vladimir; Benhamou, Simone; Castellsagu X.; Canova, Cristina; Conway, David I.; Fabiov Eleona; Forova, Lenka; Janout, Vladim; Healy, Claire M.; Holcov Ivana; Kjheim, Kristina; Lagiou, P. D.; Lissowska, Jolanta; Lowry, Raymond J.; Macfarlane, Tatiana Victorovna; Mate?, Dana; Richiardi, Lorenzo; Rudnai, Per; Szeszenia-Da?browska, Neonila; Zaridze, David Georgievich; Znaor, Ariana; Lathrop, Mark G.; Brennan, Paul J.; Bandinelli, Stefania S.; Frayling, Tim M.; Guralnik, Jack Michael D.; Milaneschi, Yuri; Perry, John R.B.; Altshuler, David M.; Elosua, Roberto; Kathiresan, Sekar; Lucas, Gavin; Melander, Olle; O'Donnell, Christopher J.; Schwartz, Stephen Marc; Voight, Benjamin F.; Smit, Johannes Hendrikus; de Geus, Eco J.C.N.; Chanock, Stephen J.; Gu, Fangyi; Hankinson, Susan E.; Hunter, D. J.; Chasman, Daniel I.; Everett, Brendan M.; Par Guillaume; Ridker, Paul M.; Li, Mingding; Maes, Hermine H.M.; Audrain-McGovern, Janet E.; Posthuma, Danile; Thornton, Laura M.; Lerman, Caryn E.; Rose, Jed E.; Ioannidis, John P.A.; Kraft, Peter L.; Lin, Danyu; Liu, Jason S.; Tozzi, Federica; Waterworth, Dawn M.; Pillai, Sreekumar G.; Muglia, Pierandrea; Middleton, Lefkos T.; Berrettini, Wade H.; Knouff, Christopher W.; Yuan, Xin; Waeber, Gard; Vollenweider, Peter K.; Preisig, Martin A.; Wareham, Nicholas J.; Zhao, Jinghua; Loos, Ruth J.f.; Barroso, In E.; Khaw, Kay Tee T.; Grundy, Scott M.; Barter, Philip J.; Mahley, Robert W.; Kesaniemi, YrjAntero; McPherson, Ruth M.; Vincent, John B.; Strauss, John S.; Kennedy, James Lowery; Farmer, Anne E.; McGuffin, Peter; Day, Richard K.; Matthews, Keith; Bakke, Per Sigvald; Gulsvik, Amund; Lucae, Susanne; Ising, Marcus; Brueckl, Tanja M.; Horstmann, Sonja; Heinrich, Joachim; Lamina, Claudia; Polaek, Ozren; Zgaga, Lina; Huffman, Jennifer E.; Campbell, Susan; Kooner, Jaspal Singh; Chambers, John Campbell; Burnett, Mary Susan; Devaney, Joseph M.; Pichard, Augusto Descalzi; Kent, Kenneth M.; Satler, Lowell F.; Lindsay, Joseph M.; Waksman, Ron; Epstein, Stephen E.; Wilson, James F.; Wild, Sarah Helen; Campbell, Harry; Vitart, Vonique; Reilly, Muredach P.; Li, Mingyao; Qu, Liming; Wilensky, Robert L.; Matthai, William H.; Honarson, Hon H.; Rader, Daniel J.; Franke, Andre R.N.; Wittig, Michael Lee; Schaefer, Arne S.; Uda, Manuela; Terracciano, Antonio; Xiao, Xiangjun; Busonero, Fabio; Scheet, Paul A.; Schlessinger, David; St-Clair, David M.; Rujescu, Dan; Abecasis, Gonlo R.; Grabe, Hans Jgen; Teumer, Alexander; Vzke, Henry; Petersmann, Astrid; John, Ulrich; Rudan, Igor; Hayward, Caroline; Wright, Alan F.; Kolcic, Ivana; Wright, Benjamin J.; Balmforth, Anthony J.; Anderson, Carl A.; Ahmed, Tariq; Mathew, Christopher G.; Parkes, Miles; Satsangi, Jack J.; Caulfield, Mark J.; Munroe, Patricia B.; Farrall, Martin; Dominiczak, Anna F.D.; Worthington, Jane E.; Thomson, Wendy; Eyre, Stephen; Barton, Anne C.; Mooser, Vincent E.; Francks, Clyde
  Translational Psychiatry (Vol. 3) – 2013
• Comparative reactivity of the myeloperoxidase-derived oxidants hypochlorous acid and hypothiocyanous acid with human coronary artery endothelial cells
  Lloyd, Mitchell M.; Grima, Michael A.; Rayner, Benjamin Saul; Hadfield, Katrina A.; Davies, Michael J.; Hawkins, Clare L.
  Free Radical Biology and Medicine (Vol. 65) – 2013
  In the immune response, hypohalous acids are generated by activated leukocytes via the release of myeloperoxidase and the formation of H <inf>2</inf>O<inf>2</inf>. Although these oxidants have important bactericidal properties, they have also been implicated in causing tissue damage in inflammatory diseases, including atherosclerosis. Hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) are the major oxidants formed by myeloperoxidase under physiological conditions, with the ratio of these oxidants dependent on diet and smoking status. HOCl is highly reactive and causes marked cellular damage, but few data are available on the effects of HOSCN on mammalian cells. In this study, we have compared the actions of HOCl and HOSCN on human coronary artery endothelial cells (HCAEC). HOCl reacts rapidly with the cells, resulting in extensive cell death by both apoptosis and necrosis, with necrosis dominating at higher oxidant doses. In contrast, HOSCN is consumed more slowly, with cell death occurring only by apoptosis. Exposure of HCAEC to HOCl and HOSCN induces changes in mitochondrial membrane permeability, which, in the case of HOSCN, is associated with mitochondrial release of proapoptotic factors, including cytochrome c, apoptosis-inducing factor, and endonuclease G. With each oxidant, apoptosis appears to be caspase-independent, with the inactivation of caspases 3/7 observed, and pretreatment of the cells with the caspase inhibitor Z-VAD-fmk having no effect on the extent of cell death. Loss of cellular thiols, depletion of glutathione, and the inactivation of thiol-dependent enzymes, including glyceraldehyde-3-phosphate dehydrogenase, were seen with both oxidants, though to a much greater extent with HOCl. The ability of myeloperoxidase-derived oxidants to induce endothelial cell apoptosis may contribute to the formation of unstable lesions in atherosclerosis. The results with HOSCN may be particularly significant for smokers, who have elevated plasma levels of SCN-, the precursor of this oxidant. 2013 Elsevier Inc. All rights reserved.
• Regulation of vascular leak and recovery from ischemic injury by general and VE-cadherin-restricted miRNA antagonists of miR-27
  Young, Jennifer A.; Ting, Kaka; Li, Jia; Mler, Thorleif; Dunn, Louise L.; Lu, Ying; Lay, Angelina J.; Moses, Joshua; Prado-Louren, Leonel; Khachigian, Levon M.; Ng, Martin; Gregory, Philip A.; Goodall, Gregory J.; Tsykin, Anna; Lichtenstein, Ilana; Hahn, Christopher N.; Tran, Nham; Shackel, Nicholas; Kench, J. G.; McCAUGHAN, G. W.; Vadas, Mathew Alexander; Gamble, Jennifer R.
  Blood (Vol. 122/16) – 2013
  Cellular junctions are essential to the normal functioning of the endothelium and control angiogenesis, tissue leak, and inflammation. From a screen of micro RNAs (miRNAs) altered in in vitro angiogenesis, we selected a subset predicted to target junctional molecules. MiR-27a was rapidly downregulated upon stimulation of in vitro angiogenesis, and its level of expression is reduced in neovessels in vivo. The downregulation of miR-27a was essential for angiogenesis because ectopic expression of miR-27a blocked capillary tube formation and angiogenesis. MiR-27a targets the junctional, endothelial-specific cadherin, VE-cadherin. Consistent with this, vascular permeability to vascular endothelial growth factor inmice is reduced by administration of a general miR-27 inhibitor. To determine that VE-cadherin was the dominant target of miR-27a function, we used a novel technology with "Blockmirs," inhibitors that bind to themiR-27 binding site in VE-cadherin. The Blockmir CD5-2 demonstrated specificity for VE-cadherin and inhibited vascular leak in vitro and in vivo. Furthermore, CD5-2 reduced edema, increased capillary density, and potently enhanced recovery from ischemic limb injury in mice. The Blockmir technology offers a refinement in the use of miRNAs, especially for therapy. Further, targeting of endothelial junctional molecules by miRNAs has clinical potential, especially in diseases associated with vascular leak. 2013 by The American Society of Hematology.
• Role of sex steroids in angiogenesis
  Lecce, Laura; Lam, Yuen Ting; Ng, Martin K.C.
  (Vol. ) – 2013
  Sex steroids such as estrogen and testosterone are key mediators of angiogenesis. They are implicated in both physiological and pathological angiogenesis such as during the menstrual cycle, wound healing, and cancer growth and progression. Sex steroids regulate many aspects of angiogenesis through both classic genomic signaling pathways which regulate gene expression and also rapid action nongenomic pathways. In this capacity, sex steroids are able to modulate endothelial and progenitor cell functions such as proliferation, migration, and attachment, which are all essential components involved in neovascularization. Since sex steroids are known to augment angiogenesis which is vital to tumor progression and growth, common treatment of hormone-responsive tumors is through sex steroid receptor antagonists. Due to the involvement of sex steroids in necessary physiological functions as well as the potential to promote pathological angiogenesis, it is fundamental that the mechanisms behind sex steroid-mediated neovascularization are understood. Springer Science+Business Media New York 2013. All rights reserved.
• Myeloperoxidase-derived oxidants modify apolipoprotein A-I and generate dysfunctional high-density lipoproteins: Comparison of hypothiocyanous acid (HOSCN) with hypochlorous acid (HOCl)
  Hadfield, Katrina A.; Pattison, David I.; Brown, Bronwyn E.; Hou, Liming; Rye, Kerry Anne; Davies, Michael J.; Hawkins, Clare L.
  Biochemical Journal (Vol. 449/2) – 2013
  Oxidative modification of HDLs (high-density lipoproteins) by MPO (myeloperoxidase) compromises its anti-atherogenic properties, which may contribute to the development of atherosclerosis. Although it has been established that HOCl (hypochlorous acid) produced by MPO targets apoA-I (apolipoprotein A-I), the major apolipoprotein of HDLs, the role of the other major oxidant generated by MPO, HOSCN (hypothiocyanous acid), in the generation of dysfunctional HDLs has not been examined. In the present study, we characterize the structural and functional modifications of lipid-free apoA-I and rHDL (reconstituted discoidal HDL) containing apoA-I complexed with phospholipid, induced by HOSCN and its decomposition product, OCN- (cyanate). Treatment of apoA-I with HOSCN resulted in the oxidation of tryptophan residues, whereas OCN- induced carbamylation of lysine residues to yield homocitrulline. Tryptophan residues were more readily oxidized on apoA-I contained in rHDLs. Exposure of lipid-free apoA-I to HOSCN and OCN- significantly reduced the extent of cholesterol efflux from cholesterol-loaded macrophages when compared with unmodified apoA-I. In contrast, HOSCN did not affect the anti-inflammatory properties of rHDL. The ability of HOSCN to impair apoA-I-mediated cholesterol efflux may contribute to the development of atherosclerosis, particularly in smokers who have high plasma levels of SCN- (thiocyanate). The Authors Journal compilation 2013 Biochemical Society.
• Chemical modification of lysozyme, glucose 6-phosphate dehydrogenase, and bovine eye lens proteins induced by peroxyl radicals: Role of oxidizable amino acid residues
  Arenas, Andrea; Lez-Alarc, Camilo; Kogan, Marcelo Javier; Lissi, Eduardo Eduardo; Davies, Michael J.; Silva, Eduardo T.
  Chemical Research in Toxicology (Vol. 26/1) – 2013
  Chemical and structural alterations to lysozyme (LYSO), glucose 6-phosphate dehydrogenase (G6PD), and bovine eye lens proteins (BLP) promoted by peroxyl radicals generated by the thermal decomposition of 2,2?-azobis(2- amidinopropane) hydrochloride (AAPH) under aerobic conditions were investigated. SDS-PAGE analysis of the AAPH-treated proteins revealed the occurrence of protein aggregation, cross-linking, and fragmentation; BLP, which are naturally organized in globular assemblies, were the most affected proteins. Transmission electron microscopy (TEM) analysis of BLP shows the formation of complex protein aggregates after treatment with AAPH. These structural modifications were accompanied by the formation of protein carbonyl groups and protein hydroperoxides. The yield of carbonyls was lower than that for protein hydroperoxide generation and was unrelated to protein fragmentation. The oxidized proteins were also characterized by significant oxidation of Met, Trp, and Tyr (but not other) residues, and low levels of dityrosine. As the dityrosine yield is too low to account for the observed cross-linking, we propose that aggregation is associated with tryptophan oxidation and Trp-derived cross-links. It is also proposed that Trp oxidation products play a fundamental role in nonrandom fragmentation and carbonyl group formation particularly for LYSO and G6PD. These data point to a complex mechanism of peroxyl-radical mediated modification of proteins with monomeric (LYSO), dimeric (G6PD), and multimeric (BLP) structural organization, which not only results in oxidation of protein side chains but also gives rise to radical-mediated protein cross-links and fragmentation, with Trp species being critical intermediates. 2012 American Chemical Society.
• Erratum: Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) Trial (Journal of the American College of Cardiology (2012) 59 (1778-1784))
  Huijgen, Roeland; Boekholdt, S. M.; Arsenault, Beno J.; Bao, Weihang; Davaine, Jean Michel; Tabet, Fatiha; Petrides, Francine; Rye, Kerry Anne; DeMicco, David A.; Barter, Philip J.; Kastelein, Johannes Jacob Pieter; Lambert, Gilles C.
  Journal of the American College of Cardiology (Vol. 61/16) – 2013
  [No abstract available]
• Low-dose colchicine for secondary prevention of cardiovascular disease
  Nidorf, Stefan Mark; Eikelboom, John W.; Budgeon, Charley A.; Thompson, Peter Lindsay
  Journal of the American College of Cardiology (Vol. 61/4) – 2013
  Objectives: The objective of this study was to determine whether colchicine 0.5 mg/day can reduce the risk of cardiovascular events in patients with clinically stable coronary disease. Background: The presence of activated neutrophils in culprit atherosclerotic plaques of patients with unstable coronary disease raises the possibility that inhibition of neutrophil function with colchicine may reduce the risk of plaque instability and thereby improve clinical outcomes in patients with stable coronary disease. Methods: In a clinical trial with a prospective, randomized, observer-blinded endpoint design, 532 patients with stable coronary disease receiving aspirin and/or clopidogrel (93%) and statins (95%) were randomly assigned colchicine 0.5 mg/day or no colchicine and followed for a median of 3 years. The primary outcome was the composite incidence of acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke. The primary analysis was by intention-to-treat. Results: The primary outcome occurred in 15 of 282 patients (5.3%) who received colchicine and 40 of 250 patients (16.0%) assigned no colchicine (hazard ratio: 0.33; 95% confidence interval [CI] 0.18 to 0.59; p < 0.001; number needed to treat: 11). In a pre-specified secondary on-treatment analysis that excluded 32 patients (11%) assigned to colchicine who withdrew within 30 days due to intestinal intolerance and a further 7 patients (2%) who did not start treatment, the primary outcome occurred in 4.5% versus 16.0% (hazard ratio: 0.29; 95% CI: 0.15 to 0.56; p < 0.001). Conclusions: Colchicine 0.5 mg/day administered in addition to statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease. 2013 American College of Cardiology Foundation.
• Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: Relationship with lipoprotein response to antiproteinuric treatment
  Kwakernaak, Arjan J.; Lambert, Gilles; Slagman, Maartje C.J.; Waanders, Femke; Laverman, Gozewijn Dirk; Petrides, Francine; Dikkeschei, Bert D.; Navis, Gerjan; Dullaart, Robin P.F.
  Atherosclerosis (Vol. 226/2) – 2013
  Objective: LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria. The proprotein convertase subtilisin-kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation. We tested whether plasma PCSK9 is elevated in proteinuric states, and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction. Methods: Thirty-nine kidney patients (e-GFR 61 29 mL/min/1.73 m2, proteinuria 1.9 [0.9-3.3] g/day; 19 on statin treatment) were studied during 2 randomized double-blind 6-week periods on either lisinopril (40 mg/day) and a regular sodium diet (194 49 mmol Na+/day; baseline treatment) or lisinopril plus valsartan (320 mg/day) and a low sodium diet (102 52 mmol Na+/day; maximal treatment), and compared to age- and sex-matched controls. Maximal treatment decreased proteinuria to 0.5 [0.3-1.1] g/day (P < 0.001). Results: Plasma PCSK9 was increased at baseline in proteinuric subjects (213 [161-314] vs. 143 [113-190] ug/L in controls, P ? 0.001), irrespective of statin use, e-GFR and BMI. PCSK9 correlated with proteinuria at baseline (R = 0.399, P = 0.018) and at maximal antiproteinuric treatment (R = 0.525, P = 0.001), but did not decrease during proteinuria reduction (P = 0.84). Individual changes in total cholesterol (R = 0.365, P = 0.024), non-HDL cholesterol (R = 0.333, P = 0.041), and LDL cholesterol (R = 0.346, P = 0.033) were correlated positively with individual PCSK9 responses. PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment (P = 0.04). Conclusion: Plasma PCSK9 was elevated in proteinuria, predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction. Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects. 2012 Elsevier Ireland Ltd.
• Dietary Sphingomyelin Lowers Hepatic Lipid Levels and Inhibits Intestinal Cholesterol Absorption in High-Fat-Fed Mice
  Chung, Rosanna W.S.; Kamili, Alvin; Tandy, Sally; Weir, Jacquelyn M.; Gaire, Raj K.; Wong, Gerard; Meikle, Peter J.; Cohn, Jeffrey S.; Rye, Kerry Anne
  PLOS ONE (Vol. 8/2) – 2013
  Controlling intestinal lipid absorption is an important strategy for maintaining lipid homeostasis. Accumulation of lipids in the liver is a major risk factor for metabolic syndrome and nonalcoholic fatty liver disease. It is well-known that sphingomyelin (SM) can inhibit intestinal cholesterol absorption. It is, however, unclear if dietary SM also lowers liver lipid levels. In the present study (i) the effect of pure dietary egg SM on hepatic lipid metabolism and intestinal cholesterol absorption was measured with [14C]cholesterol and [3H]sitostanol in male C57BL/6 mice fed a high-fat (HF) diet with or without 0.6% wt/wt SM for 18 days; and (ii) hepatic lipid levels and gene expression were determined in mice given a HF diet with or without egg SM (0.3, 0.6 or 1.2% wt/wt) for 4 weeks. Mice supplemented with SM (0.6% wt/wt) had significantly increased fecal lipid and cholesterol output and reduced hepatic [14C]cholesterol levels after 18 days. Relative to HF-fed mice, SM-supplemented HF-fed mice had significantly lower intestinal cholesterol absorption (-30%). Liver weight was significantly lower in the 1.2% wt/wt SM-supplemented mice (-18%). Total liver lipid (mg/organ) was significantly reduced in the SM-supplemented mice (-33% and -40% in 0.6% wt/wt and 1.2% wt/wt SM, respectively), as were triglyceride and cholesterol levels. The reduction in liver triglycerides was due to inactivation of the LXR-SREBP-1c pathway. In conclusion, dietary egg SM has pronounced hepatic lipid-lowering properties in mice maintained on an obesogenic diet. 2013 Chung et al.
• Olive (Olea europaea L.) Leaf Polyphenols Improve Insulin Sensitivity in Middle-Aged Overweight Men: A Randomized, Placebo-Controlled, Crossover Trial
  de Bock, Martin I.; Derraik, JosG.B.; Brennan, Christine M.; Biggs, Janene B.; Morgan, Philip E.; Hodgkinson, Stephen C.; Hofman, Paul Leslie; Cutfield, Wayne Stephen
  PLOS ONE (Vol. 8/3) – 2013
  Background: Olive plant leaves (Olea europaea L.) have been used for centuries in folk medicine to treat diabetes, but there are very limited data examining the effects of olive polyphenols on glucose homeostasis in humans. Objective: To assess the effects of supplementation with olive leaf polyphenols (51.1 mg oleuropein, 9.7 mg hydroxytyrosol per day) on insulin action and cardiovascular risk factors in middle-aged overweight men. Design: Randomized, double-blinded, placebo-controlled, crossover trial in New Zealand. 46 participants (aged 46.45.5 years and BMI 28.02.0 kg/m2) were randomized to receive capsules with olive leaf extract (OLE) or placebo for 12 weeks, crossing over to other treatment after a 6-week washout. Primary outcome was insulin sensitivity (Matsuda method). Secondary outcomes included glucose and insulin profiles, cytokines, lipid profile, body composition, 24-hour ambulatory blood pressure, and carotid intima-media thickness. Results: Treatment evaluations were based on the intention-to-treat principle. All participants took >96% of prescribed capsules. OLE supplementation was associated with a 15% improvement in insulin sensitivity (p = 0.024) compared to placebo. There was also a 28% improvement in pancreatic ?-cell responsiveness (p = 0.013). OLE supplementation also led to increased fasting interleukin-6 (p = 0.014), IGFBP-1 (p = 0.024), and IGFBP-2 (p = 0.015) concentrations. There were however, no effects on interleukin-8, TNF-?, ultra-sensitive CRP, lipid profile, ambulatory blood pressure, body composition, carotid intima-media thickness, or liver function. Conclusions: Supplementation with olive leaf polyphenols for 12 weeks significantly improved insulin sensitivity and pancreatic ?-cell secretory capacity in overweight middle-aged men at risk of developing the metabolic syndrome. Trial Registration: Australian New Zealand Clinical Trials Registry #336317. 2013 de Bock et al.
• In vitro androgen bioassays as a detection method for designer androgens
  Cooper, Elliot R.; McGrath, Kristine C.Y.; Heather, Alison Kay
  Sensors (Vol. 13/2) – 2013
  Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping. 2013 by the authors; licensee MDPI, Basel, Switzerland.
• Magnetic Resonance Imaging Detects Placental Hypoxia and Acidosis in Mouse Models of Perturbed Pregnancies
  Bobek, Gabriele; Stait-Gardner, Timothy; Surmon, Laura; Makris, Angela; Lind, Joanne Maree; Price, William S.; Hennessy, Annemarie
  PLOS ONE (Vol. 8/3) – 2013
  Endothelial dysfunction as a result of dysregulation of anti-angiogenic molecules secreted by the placenta leads to the maternal hypertensive response characteristic of the pregnancy complication of preeclampsia. Structural abnormalities in the placenta have been proposed to result in altered placental perfusion, placental oxidative stress, cellular damage and inflammation and the release of anti-angiogenic compounds into the maternal circulation. The exact link between these factors is unclear. Here we show, using Magnetic Resonance Imaging as a tool to examine placental changes in mouse models of perturbed pregnancies, that T<inf>2</inf> contrast between distinct regions of the placenta is abolished at complete loss of blood flow. Alterations in T<inf>2</inf> (spin-spin or transverse) relaxation times are explained as a consequence of hypoxia and acidosis within the tissue. Similar changes are observed in perturbed pregnancies, indicating that acidosis as well as hypoxia may be a feature of pregnancy complications such as preeclampsia and may play a prominent role in the signalling pathways that lead to the increased secretion of anti-angiogenic compounds. 2013 Bobek et al.
• High-density lipoproteins suppress chemokine expression and proliferation in human vascular smooth muscle cells
  van der Vorst, Emiel P.C.; Vanags, Laura Z.; Dunn, Louise L.; Prosser, Hamish C.G.; Rye, Kerry Anne; Bursill, C. A.
  FASEB Journal (Vol. 27/4) – 2013
  The inflammatory chemokines CCL2, CCL5, and CX3CL1 stimulate vascular smooth muscle cell (SMC) proliferation. High-density lipoproteins (HDLs) exhibit potent cardioprotective and anti-inflammatory properties. We therefore sought to determine the effect of reconstituted HDLs (rHDLs) on SMC chemokine expression and proliferation and elucidate the mechanisms. Preincubation of primary human SMCs with rHDLs containing apolipoprotein (apo)A-I and phosphatidylcholine (20 ?M, final apoA-I concentration), before stimulation with TNF-?, inhibited CCL2 (54%), CCL5 (38%), and CX3CL1 (33%) protein levels. The chemokine receptors CCR2 (29%) and CX3CR1 (22%) were also reduced by rHDLs. Incubation with rHDLs reduced the NF-?B subunit p65 in the nucleus (39%) and phosphorylated I?B? (28%), both regulators of chemokine expression. Furthermore, rHDLs inhibited the upstream signaling proteins phosphoinositide 3-kinase (37%) and phosphorylated Akt (pAkt, 49%). Incubation with rHDLs strikingly suppressed SMC proliferation (84%) and ERK phosphorylation (pERK, 29%). Finally, siRNA knockdown of the scavenger receptor SR-B1 attenuated rHDLinduced inhibition of SMC chemokine expression, p65, and proliferation, indicating that SR-B1 plays a key role in mediating these effects. Thus, rHDLs reduce SMC chemokine expression (via NF-?B/pAkt inhibition) and proliferation (via pERK inhibition). This has important implications for preventing the pathogenesis of neointimal hyperplasia, the main cause of early vein graft/stent failure.- Van der Vorst, E. P. C., Vanags, L. Z., Dunn, L. L., Prosser, H. C., Rye, K.-A., Bursill, C. A. High-density lipoproteins suppress chemokine expression and proliferation in human vascular smooth muscle cells. FASEB J. 27, 1413-1425 (2013). www.fasebj.org.
• Tropoelastin - A multifaceted naturally smart material
  Mithieux, Suzanne M.; Wise, Steven G.; Weiss, Anthony Steven
  Advanced Drug Delivery Reviews (Vol. 65/4) – 2013
  Tropoelastin dominates the physical performance of human elastic tissue as it is assembled to make elastin. Tropoelastin is increasingly appreciated as a protein monomer with a defined solution shape comprising modular, bridged regions that specialize in elasticity and cell attachment, which collectively participate in macromolecular assembly. This modular, multifaceted molecule is being exploited to enhance the physical performance and biological presentation of engineered constructs to augment and repair human tissues. These tissues include skin and vasculature, and emphasize how growing knowledge of tropoelastin can be powerfully adapted to add value to pre-existing devices like stents and novel, multi-featured biological implants. 2012 Elsevier B.V.
• Is there a role for coronary angiography in the early detection of the vulnerable plaque?
  Chan, Kim Hoe; Ng, Martin K.C.
  International Journal of Cardiology (Vol. 164/3) – 2013
  The identification of the coronary "vulnerable plaque" that is prone to disruption and thrombosis remains a "holy grail" in the treatment of coronary artery disease. The widespread use of coronary angiography for the identification of coronary atherosclerotic disease has led to numerous earlier studies exploring the role of angiography in the early detection of the vulnerable plaque. Some of the angiographic features explored for risk of plaque rupture include the degree of luminal stenosis, presence of plaque calcification, complex lesions with plaque disruption and thrombosis, and coronary artery movement patterns. However, a major limiting factor with coronary angiography is that it is a "luminogram", and provides little characterization of plaque morphology or vessel wall, both of which play an important role in the development of plaque vulnerability. Newer intravascular imaging techniques have been developed to permit more detailed interrogation of plaque morphology and vessel wall, potentially allowing for more accurate detection of plaque vulnerability. Whilst coronary angiography may be increasingly superseded by these advances in imaging technologies, it is likely that it will continue to play an important complementary role in the quest for the early detection of the vulnerable plaque. The prospective identification of the vulnerable plaque currently remains elusive, as definitive tools for its detection do not exist. Hence, further prospective studies on the natural history of the atherosclerotic plaque, as well as validation of imaging modalities in clinical studies are needed before the notion of early detection of the vulnerable plaque becomes a clinical reality. 2011 Elsevier Ireland Ltd. All rights reserved.