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Showing 1261–1280 of 2058 publications.
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Sieveking, Daniel P.; Lim, Patrick R.; Chow, Renee W.Y.; Dunn, Louise L.; Bao, Shishan San; McGrath, Kristine C.Y.; Heather, Alison Kay; Handelsman, David J.; Celermajer, David S.; Ng, Martin K.C.Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men. 2010 Sieveking et al.
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Ayer, Julian Ganesh J.; Harmer, Jason A.; Marks, Guy B.; Avolio, Alberto P.; Celermajer, David S.Objectives: Central arterial pulse wave augmentation, quantified by the augmentation index (AIx), is a key marker of arterial health, an important contributor to cardiac afterload and is significantly greater in older women than men. We measured carotid AIx in 8-year-old children to examine the influences of sex, height and arterial stiffness on central arterial pulse wave augmentation Methods: Four hundred and five children (age 8.0 0.1 years, 49% girls) had anthropometry, brachial systolic and diastolic blood pressure, heart rate and carotid artery pressure waveforms (by applanation tonometry), diastolic diameter and distensibility assessed. Results: Carotid AIx was significantly higher in girls than boys (-11.7 8.1 versus-16.5 9.3%, respectively, P < 0.001). Boys and girls had similar height (129 6 versus 128 6 cm), systolic blood pressure (100 7 versus 101 7 mmHg), diastolic blood pressure (59 6 versus 60 5 mmHg) and heart rate (80 10 versus 82 10 bpm). Carotid diastolic diameter was smaller in girls than boys (0.45 0.03 versus 0.47 0.04 cm, P < 0.001). The sex difference in AIx remained significant after adjustment for height, heart rate, blood pressure, diastolic diameter and birth weight. The time to the onset of the reflected wave was shorter in girls (155 19 versus 163 18 ms, P < 0.001). Girls had greater carotid artery distensibility (6.2 1.8 versus 5.8 1.5% per 10 mmHg, P = 0.016), suggesting lower regional carotid artery stiffness. Conclusion: Greater pulse wave augmentation in prepubertal girls results from earlier wave reflection and is independent of height, carotid artery diameter and stiffness. When combined with age-related changes in arterial compliance, this may contribute to adverse cardiovascular outcomes in older women. 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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Tabet, Fatiha; Remaley, Alan Thomas; Saliny, Aude Isabelle; Millet, Jonathan R.M.; Yan, Ling; Nakhla, Shirley; Barter, Philip J.; Rye, Kerry Anne; Lambert, GillesOBJECTIVES-: The apolipoprotein (apo)A-I mimetic peptide 5A is highly specific for ATP-binding cassette transporter (ABC)A1-mediated cholesterol efflux. We investigated whether the 5A peptide shares other beneficial features of apoA-I, such as protection against inflammation and oxidation. METHODS-: New Zealand white rabbits received an infusion of apoA-I, reconstituted high-density lipoprotein (HDL) containing apoA-I ([A-I]rHDL), or the 5A peptide complexed with phospholipids (1-palmitoyl-2-linoleoyl phosphatidylcholine [PLPC]), before inserting a collar around the carotid artery. Human coronary artery endothelial cells (HCAECs) were incubated with (A-I)rHDL or 5A/PLPC before stimulation with tumor necrosis factor ?. RESULTS-: ApoA-I, (A-I)rHDL, and 5A/PLPC reduced the collar-mediated increase in (1) endothelial expression of cell adhesion molecules vascular cell adhesion molecule-1 and intercellular adhesion molecule-1; (2) O&OV0254;2 production, as well as the expression of the Nox4 catalytic subunits of the NADPH oxidase; and (3) infiltration of circulating neutrophils into the carotid intima-media. In HCAECs, both 5A/PLPC and (A-I)rHDL inhibited tumor necrosis factor-?-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as the nuclear factor ?B signaling cascade and O&OV0254;2 production. The effects of the 5A/PLPC complex were no longer apparent in HCAECs knocked down for ABCA1. CONCLUSION-: Like apoA-I, the 5A peptide inhibits acute inflammation and oxidative stress in rabbit carotids and HCAECs. In vitro, the 5A peptide exerts these beneficial effects through interaction with ABCA1. 2010 American Heart Association, Inc.
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Dupuis, Jos; Langenberg, Claudia C.; Prokopenko, Inga I.; Meitinger, Thomas; Soranzo, Nicole; Jackson, Anne U.; Wheeler, Eleanor; Glazer, Nicole L.; Bouatia-Naji, Nabila; Gloyn, Anna L.; Lindgren, Cecilia M.; Mi, Reedik; Morris, Andrew Paul; Randall, Joshua C.; Johnson, Toby; Elliott, Paul; Rybin, Denis V.; Thorleifsson, Gudmar; Steinthsdtir, Valgerdur; Henneman, Peter; Grallert, Harald; Dehghan, Abbas; JanHottenga, Jouke; Franklin, Christopher S.; Navarro, Pau; Song, Kjioung S.; Goel, Anuj; Perry, John R.B.; Egan, Josephine M.; Lajunen, Taina K.; Grarup, Niels; Spars Thomas; Doney, Alex S.F.; Voight, Benjamin F.; Stringham, Heather M.; Li, Man; Kanoni, Stavroula; Shrader, Peter J.; Cavalcanti-Proen, Christine; Kumari, Meena; Qi, Llu; Timpson, Nicholas J.; Gieger, Christian; Zabena, Carina A.; Rocheleau, Ghislain; Ingelsson, Erik; An, Ping; O'Connell, Jeffrey R.; Luan, Jian'fan A.; Elliott, Amanda L.; McCarroll, Steven A.; Payne, Felicity; Roccasecca, Rosa Maria; Pattou, Franis N.; Sethupathy, Praveen; Ardlie, Kristin G.; Ariyek, Yavuz; Balkau, Beverley J.; Barter, Philip J.; Beilby, John P.; Ben-Shlomo, Yoav; Benediktsson, Rafn; Bennett, Amanda J.; Bergmann, Sven Michael; Bochud, Murielle; Boerwinkle, Eric A.; Bonnefond, Amie; Bonnycastle, Lori L.; Borch-Johnsen, Knut; Btcher, Yvonne; Brunner, Eric John; Bumpstead, Suzannah J.; Charpentier, Guillaume; der IdaChen, Yii; Chines, Peter S.; Clarke, Robert Joseph; McOin, Lachlan J.; Cooper, Matthew N.; Cornelis, Marylin C.; Crawford, Gabriel J.; Crisponi, Laura; Day, Ian N.M.; de Geus, Eco J.C.N.; Delplanque, Je; Dina, Christian; Erdos, Michael R.; Fedson, Annette C.; Fischer-Rosinsk Antje; Forouhi, Nita G.; Fox, Caroline S.; Frants, Rune R.; Franzosi, Maria Grazia; Gal, Pilar; Goodarzi, Mark O.; Graessler, Juergen; Groves, Christopher James; Grundy, Scott M.; Gwilliam, Rhian G.; Gyllensten, Ulf B.; Hadjadj, Samy; Hallmans, Goran; Hammond, Naomi; Han, Xijing; LiisaHartikainen, Anna; Hassanali, Neelam; Hayward, Caroline; Heath, Simon C.; Hercberg, Serge; Herder, Christian; Hicks, Andrew Anthony; Hillman, David R.; Hingorani, Aroon Dinesh; Hofman, Albert; Hui, Jennie; Hung, Joseph C.; Isomaa, Bo A.; Johnson, Paul R.V.; Jgensen, Torben J.; Jula, Antti M.; Kaakinen, Marika A.; Kaprio, Jaakko A.; AnteroKesaniemi, Y.; 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; Lyssenko, Valeriya; Mahley, Robert W.; Mangino, Massimo; Manning, Alisa Knodle; TeresaMartez-Larrad, Mar; McAteer, Jarred B.; McCulloch, Laura J.; McPherson, Ruth M.; Meisinger, Christa; Melzer, David; Meyre, David; Mitchell, Braxton D.; Morken, Mario A.; Mukherjee, Sutapa A.; Naitza, Silvia; Narisu, Narisu; Neville, Matt J.; Oostra, Ben A.; Orru, Marco; Pakyz, Ruth E.; Apalmer, Colin N.; 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; Province, Michael A.; Psaty, Bruce M.; Rathmann, Wolfgang G.; Rayner, Nigel William; Rice, Kenneth Martin; Ripatti, Samuli; Rivadeneira, Fernando R.; Roden, M. W.; Rolandsson, Olov; Sandb, Annelli; Sandhu, Manjinder Singh; Sanna, Serena; Sayer, A. A.; Scheet, Paul A.; Scott, Laura J.; Seedorf, Udo; Sharp, Stephen John; Shields, Beverley M.; Sigurson, Gunnar; Sijbrands, Eric J.G.; Silveira, Angela Maria Vidigal; Simpson, Laila; Singleton, Andrew B.; Smith, Nicholas L.; Sovio, Ulla; Swift, Amy J.; Syddall, Holly Emma; ChristineSyven, Ann; Tanaka, Toshiko; Thorand, Barbara; Tichet, Jean; Tjes, Anke; Tuomi, Tiinamaija; Uitterlinden, AndrG.; van Dijk, Ko Willems; van Hoek, Mandy; Varma, Dhiraj; Visvikis-Siest, Sophie; Vitart, Vonique; Vogelzangs, Nicole; Waeber, Gard; Wagner, Peter J.; Walley, Andrew John; BragiWalters, G.; Ward, Kim L.; Watkins, Hugh C.; Weedon, Michael N.; Wild, Sarah Helen; Willemsen, Gonneke A.H.M.; MWitteman, Jaqueline C.; GYarnell, John W.; Zeggini, Eleftheria; 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.; Hattersley, Andrew T.; 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; Morris, Andrew D.; Lind, Lars L.; Palmer, Lyle J.; Hu, Frank B.; Franks, Paul W.; Ebrahim, Shah B.J.; Marmot, M. G.; Kao, Wenhong Linda; Pankow, Jim S.; Sampson, Michael J.; Kuusisto, Johanna K.; Laakso, M. M.; Hansen, Torben Frtrup; Pedersen, Oluf Borbye; Pramstaller, Peter P.; Wichmann, Heinz-Erich Erich; Illig, Thomas; Rudan, Igor; Wright, Alan F.; Stumvoll, Michael W.; Campbell, Harry; Wilson, James F.; Bergman, Richard N.; Buchanan, Thomas A.; Collins, Francis S.; Mohlke, Karen L.; Tuomilehto, Jaakko O.I.; Valle, Timo T.; Altshuler, David M.; Rotter, Jerome I.; Siscovick, David S.; Penninx, Brenda W. J. H.; Boomsma, Dorret I.; Deloukas, Panos; Spector, Tim David; Frayling, Tim M.; Ferrucci, Luigi G.; Kong, Augustine S.; Thorsteinsdottir, Unnur; Stefsson, Ki; van Duijn, Cornelia M.; Aulchenko, Yurii S.; Cao, Antonio; Scuteri, Angelo; Schlessinger, David; Uda, Manuela; Ruokonen, Aimo O.; RiittaJarvelin, Marjo; Waterworth, Dawn M.; Vollenweider, Peter K.; Peltonen-Palotie, Leena Johanna; Mooser, Vincent E.; Abecasis, Gonlo R.; Wareham, Nicholas J.; Sladek, Robert S.; Froguel, Philippe; Watanabe, Richard M.; Meigs, James B.; Groop, Leif C.; Boehnke, Michael L.; McCarthy, Mark I.; Florez, Jose C.; Barroso, In E.
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Cohn, Jeffrey S.; Kamili, Alvin; Wat, Elaine C.L.; Chung, Rosanna W.S.; Tandy, SallyExperiments carried out with cultured cells and in experimental animals have consistently shown that phospholipids (PLs) can inhibit intestinal cholesterol absorption. Limited evidence from clinical studies suggests that dietary PL supplementation has a similar effect in man. A number of biological mechanisms have been proposed in order to explain how PL in the gut lumen is able to affect cholesterol uptake by the gut mucosa. Further research is however required to establish whether the ability of PLs to inhibit cholesterol absorption is of therapeutic benefit. 2010 by the authors.
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Chan, Kim Hoe; Wilcox, IanObstructive sleep apnea (OSA), the most common form of sleep-disordered breathing, is prevalent and frequently underdiagnosed in our community. Although presenting with predominantly respiratory symptoms, the most serious complications from OSA are cardiovascular, including arrhythmias, disease of the sinus node and conducting system, and sudden cardiac death. The acute and chronic effects of OSA on the cardiovascular system, which include major effects on autonomic function during sleep and wakefulness, are potent contributors to the development and persistence of cardiac arrhythmias. Although large randomized studies are currently lacking, treatment of OSA may be an important primary or additional therapy to supplement the use of drugs or devices in the treatment of cardiac arrhythmias. 2010 Expert Reviews Ltd.
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Chan, Dick C.F.; Hamilton, Sandra J.; Rye, Kerry Anne; Chew, Gerard Tse Jiun; Jenkins, Alicia J.; Lambert, Gilles; Watts, Gerald F.Aim: Diabetic dyslipidaemia, characterized by hypertriglyceridaemia as a result of elevated serum very-low-density lipoprotein (VLDL) concentrations, contributes to the increased risk of cardiovascular disease (CVD) in type 2 diabetes (T2DM). Proprotein convertase subtilisin/kexin type 9 (PCSK9) may play a role in regulating VLDL metabolism. We investigated the effect of fenofibrate on serum PCSK9 and VLDL particle concentrations in T2DM patients already receiving statin therapy.Methods: In a double-blind randomized crossover study, 15 statin-treated T2DM patients (63 8 years, body mass index (BMI) 29 3 kg/m2) were treated with fenofibrate (145 mg/day) or matching placebo for 12 weeks. Serum PCSK9 concentrations were measured by immunoassay. VLDL particle concentration and size were determined by nuclear magnetic resonance spectroscopy.Results: Fenofibrate decreased serum triglycerides (-23%), VLDL-triglycerides (-51%), total cholesterol (-11%), LDL-cholesterol (-16%), apolipoprotein B-100 (-16%), apolipoprotein C-III (-20%) and PCSK9 (-13%) concentrations compared with placebo (p < 0.05). Fenofibrate also decreased serum concentrations of large (-45%), medium (-66%) and small VLDL (-67%) particles (p < 0.05), without altering VLDL particle size. Serum PCSK9 reduction correlated with decreases in total (r = 0.526, p = 0.044) and small (r = 0.629, p = 0.021) VLDL particle concentrations.Conclusions: Fenofibrate concomitantly decreased serum PCSK9 and VLDL particle concentrations in statin-treated T2DM patients. These findings support a mechanistic link between PCSK9 and VLDL metabolism, possibly through an effect of PSK9 on VLDL receptor degradation. 2010 Blackwell Publishing Ltd.
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Prosser, Hamish C.G.; Richards, Arthur Mark; Forster, Malcolm E.; Pemberton, C. J.ProAngiotensin-12 (PA12) is the most recent peptide to be identified as a functional component of the renin-angiotensin system (RAS). PA12 is reported to constrict rat coronary arteries and the aorta, dependent upon angiotensin II-converting enzyme 1 (ACE1) and chymase. The current study employed myography to determine the direct vascular effects of PA12 on a range of isolated rat arteries extending from the core to periphery. PA12 significantly constricted the descending thoracic aorta, right and left commoncarotid arteries, abdominal aorta and superior mesenteric artery, with little effect on the femoral and renal arteries. AngII was found to produce similar responses to PA12 when administered at the same dose. A potency gradient in response to PA12 was clearly apparent, with vessels in closest proximity to the heart responding with the greatest constriction; while constrictive potency was lost further form the heart. Inhibition of ACE1 and chymase both significantly attenuated PA12-induced vasoconstriction, with chymostatin displaying lesser potency. We postulate ACE1 primarily regulates RAS activity within the circulation, while chymase may have an important role in local, tissue-based RAS activity. 2010 Elsevier Inc.
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McGrath, Kristine C.Y.; Hill, Michelle D.; McRobb, Lucinda S.; Heather, Alison Kay; Heather, Alison K.Background: Anecdotal evidence suggests that male sex hormones are proatherogenic. We hypothesized that the male sex hormone receptor, the androgen receptor (AR), acts as a molecular switch in sex-specific inflammatory signaling in vascular cells. Materials and methods: AR expression in human umbilical vein endothelial cells (HUVECs), human monocyte-derived macrophages (MDMs) or HeLa cells was modulated by transfection with AR siRNA or human AR cDNA expression vector. Activity and expression levels were measured by luciferase reporter assays, Western blotting or real-time PCR analysis. Results: AR knockdown reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in genetically male HUVECs. Conversely, AR upregulation in genetically female HUVECs induced VCAM-1 expression and increased dihydrotestos-terone-stimulated monocyte adhesion. Co-transfection of an AR expression vector with VCAM-1 or NF-kB-reporter vectors into phenotypically female, AR-negative HeLa cells confirmed AR regulation of VCAM-1 expression as well as AR activation of NF-kB. AR upregulation was not sufficient to increase ICAM-1 levels in female HUVECs or lipoprotein metabolism gene expression in female MDMs, despite AR knockdown limiting expression in their male counterparts. Conclusions: AR acts as a molecular switch to induce VCAM-1 expression. Low AR levels in female HUVECs limit NF-kB/VCAM-1 induction and monocyte adhesion and could contribute to the gender bias in cardiovascular disease. Unidentified factors in female cells limit induction of other proatherogenic genes not primarily regulated by NF-kB. 2010, by Walter de Gruyter Berlin New York. All rights reserved.
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Laurila, Pirkka Pekka P.; Naukkarinen, Jussi; Kristiansson, Kati; Ripatti, Samuli; Kauttu, Tuuli M.E.; Silander, Kaisa; Salomaa, Veikko V.; Perola, Markus; Karhunen, Pekka J.; Barter, Philip J.; Ehnholm, Christian P.; Peltonen-Palotie, Leena JohannaOBJECTIVE-: USF1 is a ubiquitous transcription factor governing the expression of numerous genes of lipid and glucose metabolism. APOA5 is a well-established candidate gene regulating triglyceride (TG) levels and has been identified as a downstream target of upstream stimulatory factor. No detailed studies about the effect of APOA5 on atherosclerotic lesion formation have been conducted, nor has its potential interaction with USF1 been examined. METHODS AND RESULTS-: We analyzed allelic variants of USF1 and APOA5 in families (n=516) ascertained for atherogenic dyslipidemia and in an autopsy series of middle-aged men (n=300) with precise quantitative measurements of atherosclerotic lesions. The impact of previously associated APOA5 variants on TGs was observed in the dyslipidemic families, and variant rs3135506 was associated with size of fibrotic aortic lesions in the autopsy series. The USF1 variant rs2516839, associated previously with atherosclerotic lesions, showed an effect on TGs in members of the dyslipidemic families with documented coronary artery disease. We provide preliminary evidence of gene-gene interaction between these variants in an autopsy series with a fibrotic lesion area in the abdominal aorta (P=0.0028), with TGs in dyslipidemic coronary artery disease subjects (P=0.03), and with high-density lipoprotein cholesterol (P=0.008) in a large population cohort of coronary artery disease patients (n=1065) in which the interaction for TGs was not replicated. CONCLUSION-: Our findings in these unique samples reinforce the roles of APOA5 and USF1 variants on cardiovascular phenotypes and suggest that both genes contribute to lipid levels and aortic atherosclerosis individually and possibly through epistatic effects. 2010 American Heart Association, Inc.
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Imaizumi, Satoshi; Kiya, Yoshihiro; Miura, Shinichiro; Zhang, Bo; Matsuo, Yoshino; Uehara, Yoshinari; Rye, Kerry Anne; Saku, KeijiroReconstituted (r) high-density lipoprotein (HDL) protects against coronary artery disease by promoting reverse cholesterol transport (RCT), thereby preventing atherosclerosis. In addition, rHDL has many pleiotropic effects, such as anti-oxidant, anti-inflammatory, and anti-thrombotic properties. In this study, the effects of chronic rHDL administration on blood pressure (BP), plasma lipoprotein, and charge-based HDL subfractions were examined. Thirteen male spontaneously hypertensive rats (SHRs) were randomly divided into two groups [control group (n=6) and rHDL group (n=7)] which received infusions of placebo [phosphate-buffered saline (PBS)] or rHDL (containing apolipoprotein A-I 6 mgkg) administered intravenously every other day for 3 weeks. Systolic blood pressure (SBP) was measured regularly every 4 days from the beginning of the study. Three weeks after the beginning of the study, cardiac functions were recorded by echocardiography and plasma samples were collected. Although there were no significant differences in SBP, cardiac functions, or biochemical parameters between the two groups, intermediate-migrating HDL (iHDL) in the rHDL group (0.68 0.04) was significantly lower than that in the control group (0.81 0.03) based on an analysis by capillary isotachophoresis. In conclusion, chronic administration of rHDL decreased iHDL. Further investigations are needed to understand the mechanisms by which rHDL affects lipid profiles and its relation to clinical outcomes. Copyright Informa UK Ltd.
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Wang, Yutang; Liu, Hanzhong; McKenzie, Gavin; Witting, Paul Kenneth; Stasch, Johannes Peter; Hahn, Michael G.; Changsirivathanathamrong, Dechaboon; Wu, Ben Jing; Ball, Helen J.; Thomas, Shane R.; Kapoor, Vimal; Celermajer, David S.; Mellor, Andrew L.; Keaney, John F.; Hunt, Nicholas H.; Stocker, RolandControl of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-?, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone. 2010 Nature America, Inc. All rights reserved.
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de Souza, Juliana Asceno; Vindis, Cile; Nre-Salvayre, Anne; Rye, Kerry Anne; Couturier, Martine; Thond, Patrice; Chantepie, Sandrine; Salvayre, Robert S.; Chapman, Martin John; Kontush, Anatol S.Plasma high-density lipoproteins (HDLs) protect endothelial cells against apoptosis induced by oxidized low-density lipoprotein (oxLDL). The specific component(s) of HDLs implicated in such cytoprotection remain(s) to be identified. Human microvascular endothelial cells (HMEC-1) were incubated with mildly oxLDL in the presence or absence of each of five physicochemically distinct HDL subpopulations fractionated from normolipidemic human plasma (n=7) by isopycnic density gradient ultracentrifugation. All HDL subfractions protected HMEC-1 against oxLDL-induced primary apoptosis as revealed by nucleic acid staining, annexin V binding, quantitative DNA fragmentation, inhibition of caspase-3 activity and reduction of cytoplasmic release of cytochrome c and apoptosis-inducing factor. Small, dense HDL 3c displayed twofold superior intrinsic cytoprotective activity (as determined by mitochondrial dehydrogenase activity) relative to large, light HDL 2b on a per particle basis (P < 0.05). Equally, all HDL subfractions attenuated intracellular generation of reactive oxygen species (ROS); such anti-oxidative activity diminished from HDL 3c to HDL 2b. The HDL protein moiety, in which apolipoprotein A-I (apoA-I) predominated, accounted for ?70% of HDL anti-apoptotic activity. Furthermore, HDL reconstituted with apoA-I, cholesterol and phospholipid potently protected HMEC-1 from apoptosis. By contrast, modification of the content of sphingosine-1-phosphate in HDL did not significantly alter cytoprotection. We conclude that small, dense, lipid-poor HDL 3 potently protects endothelial cells from primary apoptosis and intracellular ROS generation induced by mildly oxLDL, and that apoA-I is pivotal to such protection. 2009 The Authors Journal compilation 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
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Koelsch, Maud; Mallak, Roger; Graham, Garry G.; Kajer, Tracey B.; Milligan, Marian K.; Nguyen, Ly Q.; Newsham, Dawn W.; Keh, Jeremy S.; Kettle, Anthony James; Scott, Kieran F.; Ziegler, J. B.; Pattison, David I.; Fu, Shanlin; Hawkins, Clare L.; Rees, Martin D.; Davies, Michael J.The heme peroxidase enzyme myeloperoxidase (MPO) is released by activated neutrophils and monocytes, where it uses hydrogen peroxide (H<inf>2</inf>O<inf>2</inf>) to catalyze the production of the potent oxidants hypochlorous acid (HOCl), hypobromous acid (HOBr) and hypothiocyanous acid (HOSCN) from halide and pseudohalide (SCN-) ions. These oxidants have been implicated as key mediators of tissue damage in many human inflammatory diseases including atherosclerosis, asthma, rheumatoid arthritis, cystic fibrosis and some cancers. It is shown here that acetaminophen (paracetamol), a phenol-based drug with analgesic and antipyretic actions, is an efficient inhibitor of HOCl and HOBr generation by isolated MPO-H<inf>2</inf>O<inf>2</inf>-halide systems. With physiological halide concentrations, acetaminophen concentrations required for 50% inhibition of oxidant formation (IC<inf>50</inf>) were 776?M (100mMCl-) and 922?M (100mMCl- plus 100?MBr-), as measured by trapping of oxidants with taurine. The IC<inf>50</inf> for inhibition of HOCl generation by human neutrophils was ca. 100?M. These values are lower than the maximal therapeutic plasma concentrations of acetaminophen (?150?M) resulting from typical dosing regimes. Acetaminophen did not diminish superoxide generation by neutrophils, as measured by lucigenin-dependent chemiluminescence. Inhibition of HOCl production was associated with the generation of fluorescent acetaminophen oxidation products, consistent with acetaminophen acting as a competitive substrate of MPO. Inhibition by acetaminophen was maintained in the presence of heparan sulfate and extracellular matrix, materials implicated in the sequestration of MPO at sites of inflammation in vivo. Overall, these data indicate that acetaminophen may be an important modulator of MPO activity in vivo. 2009 Elsevier Inc.
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Thornton, Charlene Eliza; Makris, Angela; Ogle, Robert F.; Tooher, Jane M.; Hennessy, AnnemarieThe presence of proteinuria is not essential to the diagnosis of pre-eclampsia under many diagnostic consensus statements. The aim of the present study was to assess maternal and perinatal outcomes after proteinuric pre-eclampsia compared with other non-proteinuric disease presentations. 2. An individual patient data review (n = 670) was undertaken for 2003-2006 at a tertiary referral centre in Sydney (NSW, Australia). Women were diagnosed in accordance with the Australasian Society for the Study of Hypertension in Pregnancy Consensus Statement. Data were analysed with the Chi-squared test, t-tests and non-parametric tests. Statistical significance was set at P < 0.05. 3. The proteinuric cohort had higher systolic and diastolic blood pressure recordings than the non-proteinuric cohort (160/102 and 149/94 mmHg, respectively; P < 0.001), and were also administered magnesium sulphate more frequently (44 vs 22%, respectively; P < 0.001), delivered at earlier gestation (37 vs 38 weeks, respectively; P < 0.001), required operative delivery more frequently (63 vs 48%, respectively; P < 0.001) and received more antihypertensive medications during the antenatal period (72 vs 57%, respectively; P < 0.001). Acute renal failure and acute pulmonary oedema were rare. Four cases of eclampsia all occurred in non-proteinuric women. The perinatal mortality rate was lower for the offspring of women with proteinuric pre-eclampsia compared with offspring of non-proteinuric women (13/1000 and 31/1000, respectively; P = 0.006). 4. The results of the present study indicate that the presence of proteinuria denotes a group of women who have higher antenatal blood pressure, who deliver at earlier gestation and require operative delivery more commonly, although it is not an indicator of other markers of maternal morbidity or perinatal mortality. 2010 Blackwell Publishing Asia Pty Ltd.
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Rahmanto, Aldwin Suryo; Morgan, Philip E.; Hawkins, Clare L.; Davies, Michael J.Hydroperoxides are major products of the reactions of radicals and singlet oxygen with amino acids, peptides, and proteins. These species can generate radicals in the presence of metal ions and oxidize thiols via nonradical reactions, but the effects of these materials on cells are poorly understood. In this study the exposure of murine macrophage-like cells to preformed peptide or protein hydroperoxides is shown to result in hydroperoxide consumption and cellular thiol oxidation; these effects precede loss of cell viability. N-acetyltryptophan methyl ester hydroperoxides, but not the decomposed species, decreased total cellular thiols and GSH, with the latter occurring more rapidly. Time-dependent inhibition of lysosomal cathepsins B and L was also observed, together with diminished caspase 3/7 activity. A number of other cytosolic thiol- and non-thiol-dependent enzymes were not affected significantly. Hydroperoxides formed on BSA did not deplete total thiols or GSH within cells, although such reactions are rapid in model systems. In contrast, selective inhibition of cathepsins B and L (but not cathepsin D or arylsulfatase) of the endosomal-lysosomal system was detected, consistent with localization within these compartments. Decomposed BSA hydroperoxides did not induce these effects, indicating a requirement for the hydroperoxide group. The differences between these hydroperoxides are ascribed to their mechanisms of penetration into cells. Overall these studies provide valuable data on the initial cellular events arising from exposure to exogenous protein and amino acid peroxides and indicate that cellular thiols are a major target. This selective oxidation may modulate cellular redox balance and subsequent cell behavior. 2010 Elsevier Inc.
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Nobourt, Estelle; Tabet, Fatiha; Lambert, Gilles; Puranik, Rajesh; Bao, Shishan San; Yan, Ling; Davies, Michael J.; Brown, Bronwyn E.; Jenkins, Alicia J.; Dusting, Gregory James; Bonnet, David J.; Curtiss, Linda K.; Barter, Philip J.; Rye, Kerry AnneObjective: The goal of this study was to investigate the effects of nonenzymatic glycation on the antiinflammatory properties of apolipoprotein (apo) A-I. Methods and results: Rabbits were infused with saline, lipid-free apoA-I from normal subjects (apoA-I<inf>N</inf>), lipid-free apoA-I nonenzymatically glycated by incubation with methylglyoxal (apoA-I <inf>Glyc in vitro</inf>), nonenzymatically glycated lipid-free apoA-I from subjects with diabetes (apoA-I<inf>Glyc in vivo</inf>), discoidal reconstituted high-density lipoproteins (rHDL) containing phosphatidylcholine and apoA-I <inf>N</inf>, (A-IN)rHDL, or apoA-IGlyc in vitro, (A-I <inf>Glyc in vitro</inf>)rHDL. At 24 hours postinfusion, acute vascular inflammation was induced by inserting a nonocclusive, periarterial carotid collar. The animals were euthanized 24 hours after the insertion of the collar. The collars caused intima/media neutrophil infiltration and increased endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). ApoA-I<inf>N</inf> infusion decreased neutrophil infiltration and VCAM-1 and ICAM-1 expression by 89%, 90%, and 66%, respectively. The apoA-IGlyc in vitro infusion decreased neutrophil infiltration by 53% but did not reduce VCAM-1 or ICAM-1 expression. ApoA-IGlyc in vivo did not inhibit neutrophil infiltration or adhesion molecule expression. (A-I<inf>Glyc in vitro</inf>)rHDL also inhibited vascular inflammation less effectively than (A-IN)rHDL. The reduced antiinflammatory properties of nonenzymatically glycated apoA-I were attributed to a reduced ability to inhibit nuclear factor-?B activation and reactive oxygen species formation. Conclusion: Nonenzymatic glycation impairs the antiinflammatory properties of apoA-I. 2010 American Heart Association, Inc.
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Cohn, Jeffrey S.; Kamili, Alvin; Wat, Elaine C.L.; Chung, Rosanna W.S.; Tandy, SallyA number of different food components are known to reduce plasma and LDL-cholesterol levels by affecting intestinal cholesterol absorption. They include: soluble fibers, phytosterols, saponins, phospholipids, soy protein and stearic acid. These compounds inhibit cholesterol absorption by affecting cholesterol solubilization in the intestinal lumen, interfering with diffusion of luminal cholesterol to the gut epithelium and/or inhibiting molecular mechanisms responsible for cholesterol uptake by the enterocyte. Cholesterol content of intestinal chylomicrons is subsequently reduced, less cholesterol is transported to the liver within chylomicron remnants, hepatic LDL-receptor activity is increased and plasma levels of LDL-cholesterol are decreased. Reduced hepatic VLDL production and less conversion of VLDL to LDL also contribute to lower LDL levels. Certain food components may also affect intestinal bile acid metabolism. Further investigation of the way in which these functional ingredients affect intestinal lipid metabolism will facilitate their use and application as cardiovascular nutraceuticals. Crown Copyright 2010.
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Wu, Ben Jing; Yan, Ling; Charlton, Francesca; Witting, Paul Kenneth; Barter, Philip J.; Rye, Kerry AnneObjective-: To determine if niacin can confer cardiovascular benefit by inhibiting vascular inflammation and improving endothelial function independent of changes in plasma lipid and lipoprotein levels.Methods and results-: New Zealand white rabbits received normal chow or chow supplemented with 0.6% or 1.2% (wt/wt) niacin. This regimen had no effect on plasma cholesterol, triglyceride, or high-density lipoprotein levels. Acute vascular inflammation and endothelial dysfunction were induced in the animals with a periarterial carotid collar. At the 24-hour postcollar implantation, the endothelial expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemotactic protein-1 was markedly decreased in the niacin-supplemented animals compared with controls. Niacin also inhibited intima-media neutrophil recruitment and myeloperoxidase accumulation, enhanced endothelial-dependent vasorelaxation and cyclic guanosine monophosphate production, increased vascular reduced glutathione content, and protected against hypochlorous acid-induced endothelial dysfunction and tumor necrosis factor ?-induced vascular inflammation. Conclusion-: Previous human intervention studies have demonstrated that niacin inhibits coronary artery disease. This benefit is thought to be because of its ability to reduce low-density lipoprotein and plasma triglyceride levels and increase high-density lipoprotein levels. The present study showed that niacin inhibits vascular inflammation and protects against endothelial dysfunction independent of these changes in plasma lipid levels. 2010 American Heart Association, Inc.
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Liu, Jason Z.; 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; Wichmann, Heinz-Erich Erich; Rawal, Rajesh; Dahmen, Norbert; 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.; Thompson, John R.; Balmforth, Anthony J.; Hall, Alistair Scott; Samani, Nilesh J.; Anderson, Carl A.; Ahmad, 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; Marchini, Jonathan L.Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 10 19) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3. 2010 Nature America, Inc. All rights reserved.
