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Dysfunctional nitric oxide signalling increases risk of myocardial infarction
Erdmann, Jeanette1,2; Stark, Klaus3,4; Esslinger, Ulrike B.3,5; Rumpf, Philipp Moritz6,7,8; Koesling, Doris9; de Wit, Cor2,10; Kaiser, Frank J.2,11; Braunholz, Diana11; Medack, Anja1; Fischer, Marcus3; Zimmermann, Martina E.3; Tennstedt, Stephanie1; Graf, Elisabeth12,13; Eck, Sebastian12,13; Aherrahrou, Zouhair1,2; Nahrstaedt, Janja1; Willenborg, Christina1,2; Bruse, Petra1; Braenne, Ingrid1; Noethen, Markus M.14,15; Hofmann, Per14,16,17; Braund, Peter S.18,19; Mergia, Evanthia9; Reinhard, Wibke6,7,8; Burgdorf, Christof6,7; Schreiber, Stefan20; Balmforth, Anthony J.21; Hall, Alistair S.22; Bertram, Lars23; Steinhagen-Thiessen, Elisabeth24; Li, Shu-Chen25,26; Maerz, Winfried27,28,29,30; Reilly, Muredach31; Kathiresan, Sekar32,33,34,35; McPherson, Ruth36; Walter, Ulrich37,38; Ott, Jurg39,40; Samani, Nilesh J.18,19; Strom, Tim M.12,13; Meitinger, Thomas6,7,12,13; Hengstenberg, Christian6,7,8; Schunkert, Heribert6,7,8; CARDIoGRAM; Hengstenberg, C (reprint author), Deutsch Herzzentrum Munich, D-80636 Munich, Germany.
摘要Myocardial infarction, a leading cause of death intheWesternworld(1), 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(2). The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history(3). Nextgeneration sequencing in families with several affected individuals has revolutionized mutation identification(4). Here we report the segregation of two private, heterozygous mutations in two functionally relatedgenes, GUCY1A3 (p.Leu163Phefs*24) andCCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the alpha 1 subunit of soluble guanylyl cyclase (alpha 1-sGC)(5), and CCT7 encodes CCT eta, a member of the tailless complex polypeptide 1 ring complex(6), 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(7). Wedemonstratein vitro that mutations inbothGUCY1A3 and CCT7 severely reduce alpha 1-sGC as well as beta 1-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-oxideinduced cGMP formation. Mice deficient in alpha 1-sGC protein displayed accelerated thrombus formation in themicrocirculation 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.
学科领域Medical Psychology
项目资助者Deutsche Forschungsgemeinschaft ; German Federal Ministry of Education and Research (BMBF) [01GS0417, 01GS0832] ; EU [LSHM-CT-2006-037593] ; ENGAGE [201413] ; GEUVADIS [261123] ; binational BMBF/ANR funded project CARDomics [01KU0908A] ; Universitat zu Lubeck ; University Hospital of Regensburg, Germany ; The German Federal Ministry for Education and Research [16SV5538] ; NSFC from Chinese Government [30730057] ; British Heart Foundation ; Leicester NIHR Biomedical Research Unit in Cardiovascular Disease ; BMBF [01EO1003] ; DFG
项目简介We thank all the family members who participated in this research. Without the continuous support of these patients over more than 15 years, the present work would not have been possible. We would like to thank S. Wrobel, S. Stark, A. Liebers, K. Franke, J. Stegmann-Frehse, M. Behrensen, M. Schmid, J. Eckhold, D. Wollner, U. Krabbe and J. Simon for technical assistance. Furthermore, we would like to thank M. Becker, N. Buchholz, I. Demuth, R. Eckardt, H. Heekeren, U. Lindenberger, M. Lovden, L. Muller, W. Nietfeld, G. Pawelec, F. Schmiedeck, T. Siedler and G. G. Wagner for their contributions to BASE-II. We also would like to thank S. Herterich and S. Gambaryan for advice, and B. Mayer, U. Hubauer, K.-H. Ameln and A. Grosshennig for help with GerMIFS. We thank WTCCC+ and the WTCCC-CAD2 investigators for access to their data. The study is supported by the Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 (01GS0417) and NGFN-plus (01GS0832)), the FP6 and FP7 EU-funded integrated projects Cardiogenics (LSHM-CT-2006-037593), ENGAGE (201413), and GEUVADIS (261123), the binational BMBF/ANR funded project CARDomics (01KU0908A), the local focus programs 'Kardiovaskulare Genomforschung' and 'Medizinische Genetik' of the Universitat zu Lubeck, and the University Hospital of Regensburg, Germany. The German Federal Ministry for Education and Research provided funding for BASE-II (BMBF; grant no. 16SV5538). Support by NSFC grant 30730057 from the Chinese Government (to J.O.) is gratefully acknowledged. N. J. S. holds a Chair funded by the British Heart Foundation, and is supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. U. W. is supported by the BMBF(01EO1003). M. M. N. is a member of the DFG-funded Excellence Cluster ImmunoSensation.
WOS研究方向Science & Technology - Other Topics
WOS类目Multidisciplinary Sciences
WOS标题词Science & Technology
被引频次:125[WOS]   [WOS记录]     [WOS相关记录]
通讯作者Hengstenberg, C (reprint author), Deutsch Herzzentrum Munich, D-80636 Munich, Germany.
作者单位1.Med Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany
2.German Ctr Cardiovasc Res DZHK, D-23562 Lubeck, Germany
3.Univ Klinikum Regensburg, Klin & Poliklin Innere Med 2, D-93053 Regensburg, Germany
4.Univ Regensburg, Dept Genet Epidemiol, D-93053 Regensburg, Germany
5.INSERM, UMR S937, Paris, France
6.Deutsch Herzzentrum Munich, D-80636 Munich, Germany
7.Tech Univ Munich, Klinikum Rechts Isar, Med Klin 1, D-80636 Munich, Germany
8.German Ctr Cardiovasc Res DZHK, D-80636 Munich, Germany
9.Ruhr Univ Bochum, Dept Pharmacol & Toxicol, D-44801 Bochum, Germany
10.Med Univ Lubeck, Inst Physiol, D-23562 Lubeck, Germany
11.Med Univ Lubeck, Inst Humangenet, D-23562 Lubeck, Germany
12.German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany
13.Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany
14.Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany
15.Univ Bonn, Res Ctr Life & Brain, Dept Genom, D-53127 Bonn, Germany
16.Univ Basel Hosp, Div Med Genet, CH-4003 Basel, Switzerland
17.Univ Basel, Dept Biomed, CH-4003 Basel, Switzerland
18.Univ Leicester, Dept Cardiovasc Sci, Leicester LE1 7RH, Leics, England
19.Glenfield Gen Hosp, Leicester Natl Inst Hlth Res Biomed Res Unit Card, Leicester LE1 7RH, Leics, England
20.Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany
21.Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Multidisciplinary Cardiovasc Res Ctr, Div Cardiovasc & Diabet Res, Leeds LS2 9JT, W Yorkshire, England
22.Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Multidisciplinary Cardiovasc Res Ctr, Div Cardiovasc & Neuronal Remodelling, Leeds LS2 9JT, W Yorkshire, England
23.Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany
24.Charite, Charite Res Grp Geriatr, D-10117 Berlin, Germany
25.Max Planck Inst Human Dev, Ctr Lifespan Psychol, D-14195 Berlin, Germany
26.Tech Univ Dresden, Dept Psychol, D-01062 Dresden, Germany
27.Synlab Serv GmbH, Synlab Acad, D-68165 Mannheim, Germany
28.Synlab Serv GmbH, Business Dev, D-68165 Mannheim, Germany
29.Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria
30.Heidelberg Univ, Med Fac Mannheim, Med Clin 5, D-68167 Mannheim, Germany
31.Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA
32.Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02215 USA
33.Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02215 USA
34.Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02215 USA
35.Broad Inst Harvard & Massachusetts Inst Technol M, Program Med & Populat Genet, Cambridge, MA 02215 USA
36.Univ Ottawa, Inst Heart, Ottawa, ON K1Y 4W7, Canada
37.Univ Med Mainz, CTH, D-55131 Mainz, Germany
38.German Ctr Cardiovasc Res DZHK, D-55131 Mainz, Germany
39.Chinese Acad Sci, Inst Psychol, Beijing 100864, Peoples R China
40.Rockefeller Univ, Lab Stat Genet, New York, NY 10065 USA
GB/T 7714
Erdmann, Jeanette,Stark, Klaus,Esslinger, Ulrike B.,et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction[J]. NATURE,2013,504(7480).
APA Erdmann, Jeanette.,Stark, Klaus.,Esslinger, Ulrike B..,Rumpf, Philipp Moritz.,Koesling, Doris.,...&Hengstenberg, C .(2013).Dysfunctional nitric oxide signalling increases risk of myocardial infarction.NATURE,504(7480).
MLA Erdmann, Jeanette,et al."Dysfunctional nitric oxide signalling increases risk of myocardial infarction".NATURE 504.7480(2013).
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