Dysfunctional nitric oxide signalling increases risk of myocardial infarction

被引：221

作者：

Erdmann, Jeanette ^{[1
,2
]}

Stark, Klaus ^{[3
,4
]}

Esslinger, Ulrike B. ^{[3
,5
]}

Rumpf, Philipp Moritz ^{[6
,7
,8
]}

Koesling, Doris ^{[9
]}

de Wit, Cor ^{[2
,10
]}

Kaiser, Frank J. ^{[2
,11
]}

Braunholz, Diana ^{[11
]}

Medack, Anja ^{[1
]}

Fischer, Marcus ^{[3
]}

Zimmermann, Martina E. ^{[3
]}

Tennstedt, Stephanie ^{[1
]}

Graf, Elisabeth ^{[12
,13
]}

Eck, Sebastian ^{[12
,13
]}

Aherrahrou, Zouhair ^{[1
,2
]}

Nahrstaedt, Janja ^{[1
]}

Willenborg, Christina ^{[1
,2
]}

Bruse, Petra ^{[1
]}

Braenne, Ingrid ^{[1
]}

Noethen, Markus M. ^{[14
,15
]}

Hofmann, Per ^{[14
,16
,17
]}

Braund, Peter S. ^{[18
,19
]}

Mergia, Evanthia ^{[9
]}

Reinhard, Wibke ^{[6
,7
,8
]}

Burgdorf, Christof ^{[6
,7
]}

Schreiber, Stefan ^{[20
]}

Balmforth, Anthony J. ^{[21
]}

Hall, Alistair S. ^{[22
]}

Bertram, Lars ^{[23
]}

Steinhagen-Thiessen, Elisabeth ^{[24
]}

Li, Shu-Chen ^{[25
,26
]}

Maerz, Winfried ^{[27
,28
,29
,30
]}

Reilly, Muredach ^{[31
]}

Kathiresan, Sekar ^{[32
,33
,34
,35
]}

McPherson, Ruth ^{[36
]}

Walter, Ulrich ^{[37
,38
]}

Ott, Jurg ^{[39
,40
]}

Samani, Nilesh J. ^{[18
,19
]}

Strom, Tim M. ^{[12
,13
]}

Meitinger, Thomas ^{[6
,7
,12
,13
]}

Hengstenberg, Christian ^{[6
,7
,8
]}

Schunkert, Heribert ^{[6
,7
,8
]}

机构：

[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

来源：

NATURE | 2013年 / 504卷 / 7480期

关键词：

SOLUBLE GUANYLATE-CYCLASE; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; DISEASE;

D O I：

10.1038/nature12722

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：432 / +

页数：8

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