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Nature. 2013 Dec 19;504(7480):432-6. doi: 10.1038/nature12722. Epub 2013 Nov 10.

Dysfunctional nitric oxide signalling increases risk of myocardial infarction.

Collaborators (199)

Kathiresan S, Reilly MP, Samani NJ, Schunkert H, Erdmann J, Assimes TL, Boerwinkle E, Erdmann J, Hall A, Hengstenberg C, Kathiresan S, König IR, Laaksonen R, McPherson R, Reilly MP, Samani NJ, Schunkert H, Thompson JR, Thorsteinsdottir U, Ziegler A, König IR, Thompson JR, Absher D, Chen L, Cupples L, Halperin E, Li M, Musunuru K, Preuss M, Schillert A, Thorleifsson G, Voight BF, Wells GA, Absher D, Assimes TL, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Zeller T, Schillert A, Wild P, Ziegler A, Schnabel R, Sinning C, Lackner K, Tiret L, Nicaud V, Cambien F, Bickel C, Rupprecht HJ, Perret C, Proust C, Münzel T, Barbalic M, Bis J, Boerwinkle E, Chen IY, Cupples L, Dehghan A, Demissie-Banjaw S, Folsom A, Glazer N, Gudnason V, Harris T, Heckbert S, Levy D, Lumley T, Marciante K, Morrison A, O'Donnell CJ, Psaty BM, Rice K, Rotter JI, Siscovick DS, Smith N, Smith A, Taylor KD, van Duijn C, Volcik K, Whitteman J, Ramachandran V, Hofman A, Uitterlinden A, Gretarsdottir S, Gulcher JR, Holm H, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Thorleifsson G, Thorsteinsdottir U, Erdmann J, Fischer M, Grosshennig A, Hengstenberg C, König IR, Lieb W, Linsel-Nitschke P, Preuss M, Stark K, Schreiber S, Wichmann HE, Ziegler A, Schunkert H, Aherrahrou Z, Bruse P, Doering A, Erdmann J, Hengstenberg C, Illig T, Klopp N, König IR, Diemert P, Loley C, Medack A, Meisinger C, Meitinger T, Nahrstedt J, Peters A, Preuss M, Stark K, Wagner AK, Wichmann HE, Willenborg C, Ziegler A, Schunkert H, Böhm BO, Dobnig H, Grammer TB, Halperin E, Hoffmann MM, Kleber M, Laaksonen R, März W, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Voight BF, Musunuru K, Guiducci C, Burtt N, Gabriel SB, Siscovick DS, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Kathiresan S, Stewart AF, Chen L, Dandona S, Wells GA, Jarinova O, McPherson R, Roberts R, Reilly MP, Li M, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Samani NJ, Thompson JR, Braund PS, Nelson CP, Wright BJ, Balmforth AJ, Ball SG, Hall AS.

Author information

1
1] Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany [3].
2
1] Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany [2] Department of Genetic Epidemiology, University of Regensburg, 93053 Regensburg, Germany [3].
3
1] Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany [2] Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S937 Paris, France [3].
4
1] Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany [3].
5
Department of Pharmacology and Toxicology, Ruhr-University Bochum, 44801 Bochum, Germany.
6
1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany [2] Institut für Physiologie, Universität zu Lübeck, 23562 Lübeck, Germany.
7
1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany [2] Institut für Humangenetik, Universität zu Lübeck, 23562 Lübeck, Germany.
8
Institut für Humangenetik, Universität zu Lübeck, 23562 Lübeck, Germany.
9
Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany.
10
Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany.
11
1] Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany [2] Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
12
1] Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany.
13
1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Department of Genomics, Research Center Life & Brain, University of Bonn, 53127 Bonn, Germany.
14
1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, 4003 Basel, Switzerland.
15
1] Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK [2] Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE1 7RH, UK.
16
1] Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany.
17
Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany.
18
Institute of Clinical Molecular Biology, Christian-Albrecht-Universität, 24105 Kiel, Germany.
19
Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK.
20
Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK.
21
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
22
Charité Research Group on Geriatrics, Charité-Universitätsmedizin, 10117 Berlin, Germany.
23
1] Center for Lifespan Psychology, Max Planck Institute for Human Development, 14195 Berlin, Germany [2] Department of Psychology, TU Dresden, 01062 Dresden, Germany.
24
1] Synlab Academy and Business Development, synlab Services GmbH, 68165 Mannheim, Germany [2] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria [3] Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
25
The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
26
1] Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [3] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02215, USA.
27
University of Ottawa, Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
28
1] Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin Mainz, 55131 Mainz, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site RheinMain, 55131 Mainz, Germany.
29
1] Institute of Psychology, Chinese Academy of Sciences, Beijing 100864, China [2] Laboratory of Statistical Genetics, Rockefeller University, New York 10065, USA.
30
1] Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany [2] Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany [3] Institute of Human Genetics, Technische Universität München, 81675 München, Germany.

Abstract

Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.

PMID:
24213632
DOI:
10.1038/nature12722
[Indexed for MEDLINE]

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