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1. NADPH Oxidase-4 Driven Cardiac Macrophage Polarization Protects Against Myocardial Infarction–Induced Remodeling

Author

Heloise Mongue-Din, PharmD, PhD, Ashish S. Patel, PhD, Yee H. Looi, PhD, David J. Grieve, PhD, Narayana Anilkumar, PhD, Alexander Sirker, PhD, Xuebin Dong, MD, PhD, Alison C. Brewer, PhD, Min Zhang, MD, PhD, Alberto Smith, PhD, and Ajay M. Shah, MD

Subjects
cardiac, infarction, ischemia, macrophage, NADPH oxidase, remodeling, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

The reactive oxygen species–generating enzyme NADPH oxidase 4 (Nox4) is up-regulated in the heart after myocardial infarction (MI). Mice with cardiomyocyte-targeted Nox4 overexpression (TG) displayed increased macrophages in the heart at baseline, with skewing toward an M2 phenotype compared with wild-type controls (WT). After MI, TG mice had a higher proportion of M2 macrophages along with higher survival, decreased cardiac remodeling, and better contractile function than wild-type mice. The post-MI increase in cardiac matrix metalloproteinase–2 activity was substantially blunted in TG mice. These results indicate that cardiomyocyte Nox4 modulates macrophage polarization toward an M2 phenotype, resulting in improved post-MI survival and remodeling, likely through the attenuation of cardiac matrix metalloproteinase–2 activity.

Published
2017
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2. Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Author

Wolfgang Lieb, Bruna Gigante, Thodur M. Vasudevan, Georg Homuth, Joseph B. Muhlestein, Mark J. Daly, Andrew P. Morris, Jacqueline de Graaf, Peter Kraft, Ann-Kristin Petersen, André G. Uitterlinden, Jaqueline C M Witteman, Valgerdur Steinthorsdottir, Jutta Palmen, Amanda L. Elliott, Cecilia M. Lindgren, Richard N. Bergman, Benjamin D. Horne, Tony R. Merriman, Robert W. Davies, Jaspal S. Kooner, Gavin Lucas, Carl G. P. Platou, Diederick E. Grobbee, Ruth J. F. Loos, Fulvio Ricceri, Karin Leander, Wen H. L. Kao, Torsten Lauritzen, Qi Sun, Narisu Narisu, Stephan B. Felix, N. William Rayner, Aaron R. Folsom, Robert D. Sayers, Ross D. Blair, John F. Carlquist, Jing Hua Zhao, L. Vicky Phillips, Gabe Crawford, Anne Johnson, Chris Wallace, Paul F. O'Reilly, Jose C. Florez, Andreas Ziegler, Salvatore Panico, Neil R. Robertson, Ruth Frikke-Schmidt, Leif Groop, Pier Mannuccio Mannucci, Stanley L. Hazen, Gerjan Navis, Peter P. Pramstaller, Laura J. Scott, Niels Grarup, Klaus Berger, Christian Gieger, Stephen E. Epstein, Cornelia Huth, Stephanie Tennstedt, Morris J. Brown, Timothy A. Barnes, Naomi Hammond, Ulf de Faire, Vilmundur Gudnason, Marcus Fischer, Nita G. Forouhi, Paolo Vineis, Thomas Quertermous, Christopher Patterson, W.H. Wilson Tang, Konstantinos A. Papadakis, Lincoln Stein, Maciej Tomaszewski, Suthesh Sivapalaratnam, M. S. Sandhu, Feng Zhang, Christa Meisinger, David R. Lewis, Norman Klopp, Roza Blagieva, Gonçalo R. Abecasis, Jeffrey L. Anderson, Lu Qi, Amy J. Swift, Albert Hofman, George Dedoussis, Robert Luben, Daniel J. Rader, Thomas Münzel, Bert Bravenboer, Christopher J. O'Donnell, Elin Org, Veikko Salomaa, Philipp S. Wild, Stephen G. Ellis, Dawn M. Waterworth, Vesela Gateva, Loukianos S. Rallidis, Joseph M. Devaney, kevin Burnand, Robert Clarke, George A. Wells, Harold Snieder, Kay-Tee Khaw, Panos Deloukas, Jaakko Tuomilehto, Louise V. Wain, Eric Boerwinkle, Inke R. König, Amanda J. Bennett, Uwe Völker, Florian Ernst, Markus M. Nöthen, Thomas Sparsø, Jean Tichet, Inga Prokopenko, Paul Johnson, Jaume Marrugat, Marju Orho-Melander, Aloysius G Lieverse, Ian Thomson, Vincent Mooser, Teresa Ferreira, Man Li, Benjamin J. Wright, Ryan P. Welch, Alessandra Allione, Stefan Blankenberg, Veryan Codd, Philippe Froguel, James C. Engert, Pekka Jousilahti, Klaus Stark, Toby Johnson, Cornelia M. van Duijn, Ivo Gut, John J.P. Kastelein, Thomas M. Morgan, Noël P. Burtt, Laura J. McCulloch, Tim D. Spector, Peter S. Chines, Timo T. Valle, Peter Shrader, Christian Dina, Diana Zelenika, Monika Stoll, Peter S. Braund, Harry Campbell, Rainer Rettig, Joep A.W. Teijink, Thomas Illig, Anne Tybjærg-Hansen, Peter Vollenweider, Guangju Zhai, Frits R. Rosendaal, Pau Navarro, James B. Meigs, Ghislain Rocheleau, Li Chen, Pilar Galan, Giuseppe Matullo, Henry Völzke, Samer S. Najjar, Christina Loley, N. Charlotte Onland-Moret, Alison H. Goodall, Riyaz S. Patel, S. Matthijs Boekholdt, Pim van der Harst, John R. B. Perry, Angela Doering, James S. Pankow, Gudmundur Thorgeirsson, Xin Yuan, Patricia B. Munroe, Abbas Dehghan, Tamara B. Smith, Valeriya Lyssenko, Mark I. McCarthy, Andrew T. Hattersley, Simon Futers, Barbara Thorand, Andre G. Uitterlinden, Simon J. Griffin, Winfried März, Nilesh J. Samani, Frank B. Hu, Valeria Romanazzi, Michael N. Weedon, Zouhair Aherrahrou, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Markus Perola, Stefania Bandinelli, Kathy Stirrups, Hilma Holm, Maja Barbalić, Kiran Musunuru, David Couper, David S. Siscovick, Guillaume Charpentier, Alexandre F.R. Stewart, Patrick Diemert, Leena Peltonen, Serge Hercberg, Robert Roberts, Michael Roden, Rhian Gwilliam, Guillaume Lettre, Eric J.G. Sijbrands, Lambertus A. Kiemeney, Martha Ganser, Silvia Polidoro, Kristin G. Ardlie, Stephen G. Ball, Kristina Bengtsson Boström, Katharine R. Owen, Paul E. de Jong, Felicity Payne, Wendy L. McArdle, Frances M K Williams, Paul Elliott, Roberto Elosua, Devin Absher, Kristian Midthjell, Jan D. Blankensteijn, Nelson B. Freimer, John C. Chambers, G. Kolovou, Karl Andersen, John Webster, Nicholas J. Wareham, Eric E. Schadt, Simon Heath, Diana Rubin, Solveig Gretarsdottir, Willem H. Ouwehand, Oluf Pedersen, Liming Qu, Sandra Eifert, Mary Susan Burnett, Paul Burton, Frank M. van Bockxmeer, Eleftheria Zeggini, Stephen M. Schwartz, Simon C. Potter, Tiinamaija Tuomi, Jeffrey R. Gulcher, David Altshuler, Harald Grallert, Hooman Allayee, Kari Stefansson, Anne H. Child, Sekar Kathiresan, Torben Hansen, Unnur Thorsteinsdottir, Isaac Subirana, Serena Sanna, Muredach P. Reilly, J. Wouter Jukema, H.-Erich Wichmann, François Cambien, Pier Angelica Merlini, Wiek H. van Gilst, Caroline S. Fox, Andrew Smith, Oliviero Olivieri, S Sohrabi, James F. Wilson, Gillian W. Cockerill, Guanming Wu, Andrew D. Morris, Carlos Iribarren, Joshua W. Knowles, Angelo Scuteri, Göran Berglund, Marilyn C. Cornelis, Pascal P. McKeown, Thorsten Reffelmann, Gérard Waeber, Les McNoe, Maris Laan, Dilip K. Naik, Karen L. Mohlke, Matthew Waltham, Rachel E. Clough, Claudia Langenberg, Seamus C. Harrison, Hany Hafez, Timon W. van Haeften, Carlotta Sacerdote, Robert Sladek, Nicola Martinelli, Declan Bradley, Cristen J. Willer, Sarah E. Hunt, Sven Cichon, Udo Seedorf, Winston Hide, Arne Schillert, Cuno S.P.M. Uiterwaal, Steve E. Humphries, Andre A van Rij, Stéphane Cauchi, Michael Boehnke, Beverley M. Shields, Suzannah Bumpstead, Diane M. Becker, Ron Do, Heribert Schunkert, Jacques S. Beckmann, Alistair S. Hall, Mike Sampson, Christine Proença, Lachlan J. M. Coin, Rob M. van Dam, Mohan U. Sivananthan, Martin Farrall, B. Gerry Hill, Simonetta Guarrera, Thijs T. W. van Herpt, Sonia S. Anand, Peter M. Nilsson, Arne Pfeufer, Rafn Benediktsson, Candace Guiducci, Lee M. Kaplan, Michel Marre, Thomas Meitinger, Annette F. Baas, Graham A. Hitman, Roberto Lorbeer, Flora Peyvandi, David J. Hunter, Seraya Maouche, G. Mark Lathrop, Michael R. Erdos, Thomas W. Mühleisen, L. Adrienne Cupples, Anne E. Hughes, Ayellet V. Segrè, Igor Rudan, Kijoung Song, Reijo Laaksonen, G. Bragi Walters, Christopher P. Nelson, Christopher S. Franklin, Richard M. Watanabe, Mattijs E. Numans, Christina Willenborg, Jeanette Erdmann, Alessandra Di Gregorio, John M. C. Connell, Soumya Raychaudhuri, Jian'an Luan, Anthony J. Balmforth, Yurii S. Aulchenko, Arne Schäfer, Catherine M. Rice, Tanja Zeller, Grace Yu, Augustine Kong, Matthew M Thompson, Diego Ardissino, Oliver Hofmann, John R. Thompson, J.B. Wild, Alexander Teumer, Ulf Gyllensten, David P. Strachan, Martin D. Tobin, Michael A. Kaiser, Steve McCarroll, Beverley Balkau, Stephen J. Newhouse, Michael Preuss, John A. Spertus, Janja Nahrstaedt, Neelam Hassanali, Gunnar Sigurdsson, Jaapjan D. Snoep, Angela Döring, Todd Green, D. Julian A. Scott, Christian Herder, Bo Isomaa, Anne U. Jackson, David Hadley, Domenico Girelli, Jes S. Lindholt, Toshiko Tanaka, Ruth Topless, Bernhard O. Boehm, Jana V. van Vliet-Ostaptchouk, Anna-Liisa Hartikainen, Anneli Pouta, Anuj Goel, Stefan Schreiber, Kristian Hveem, Gabriel Crawford, Pierre Meneton, Jürgen Schrezenmeir, Andre M. van Rij, Markku Laakso, Richa Saxena, Joshua C. Bis, Samy Hadjadj, Anders Franco-Cereceda, Noha Lim, Christopher J. Groves, Klaus Strassburger, Stefan E Matthiasson, M. Lourdes Sampietro, Josée Dupuis, Morris J. Bown, Cisca Wijmenga, Shu Ye, Jennifer Freyer, Anders Hamsten, Christian Hengstenberg, Olle Melander, Sarah Edkins, Alberto Smith, Luigi Ferrucci, Murielle Bochud, Lori L. Bonnycastle, Gregory T. Jones, Manuela Uda, Lasse Folkersen, Timothy M. Frayling, Giovanni Tognoni, Torben Jørgensen, Anna F. Dominiczak, Michiel L. Bots, Mario A. Morken, Ian Buysschaert, Colin N. A. Palmer, Andrew Hill, Mark J. Caulfield, Nicolas Sylvius, Nicole Soranzo, Susana Eyheramendy, Christopher Newton-Cheh, Eran Halperin, Mandy van Hoek, Stephen A. Badger, Paul Scheet, Gudmar Thorleifsson, Themistocles L. Assimes, Inês Barroso, Sheila Bingham, Nour Eddine El Mokhtari, Yvonne T. van der Schouw, Andrew J. Lotery, Heather M. Stringham, Marcus Dörr, Per Eriksson, Mark Walker, Mette Refstrup, Anna L. Gloyn, Ann-Christine Syvänen, John F. Peden, Diether Lambrechts, Arshed A. Quyyumi, Katherine S. Elliott, Jonathan Golledge, Edward G. Lakatta, Serkalem Demissie, Lewis C. Becker, Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Paul Norman, Marjo-Riitta Järvelin, Annette Peters, David Schlessinger, Janet T. Powell, Surgery, ICaR - Ischemia and repair, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Male, VASCULAR WALL, Genome-wide association study, 030204 cardiovascular system & hematology, Bioinformatics, Aortic aneurysm, 0302 clinical medicine, Risk Factors, Odds Ratio, Genetics(clinical), Genetics (clinical), Aorta, 0303 health sciences, Cardiovascular diseases [NCEBP 14], Homozygote, Abdominal aortic aneurysm, Organ Specificity, Data Interpretation, Statistical, CORONARY-ARTERY-DISEASE, Female, METALLOPROTEINASE, Sterol Regulatory Element Binding Protein 1, Low Density Lipoprotein Receptor-Related Protein-1, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Locus (genetics), Biology, Polymorphism, Single Nucleotide, DISSECTIONS, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genome-wide associaton, Coronary-artery-disease, Susceptibility loci, Sequence variant, Vascular wall, Metalloproteinase, Atherosclerosis, Identification, Metaanalysis, Dissections, medicine.artery, Internal medicine, Cell Line, Tumor, medicine, Genetics, Humans, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Genetic association, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Aged, IDENTIFICATION, Case-control study, Odds ratio, medicine.disease, Endocrinology, ATHEROSCLEROSIS, SEQUENCE VARIANT, Genetic Loci, Case-Control Studies, Aortic Aneurysm, Abdominal, Follow-Up Studies, Genome-Wide Association Study
Abstract

Contains fulltext : 97601.pdf (Publisher’s version ) (Closed access) Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 x 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 x 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 x 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression. 9 p.

Published
2011
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