Dysfunctional nitric oxide signalling increases risk of myocardial infarction

Jeanette Erdmann; Klaus Stark; Ulrike B. Esslinger; Philipp Moritz Rumpf; Doris Koesling; Cor DeWit; Frank J. Kaiser; Diana Braunholz; Anja Medack; Marcus Fischer; Martina E. Zimmermann; Stephanie Tennstedt; Elisabeth Graf; Sebastian Eck; Zouhair Aherrahrou; Janja Nahrstaedt; Christina Willenborg; Petra Bruse; Ingrid Brænne; Markus M. Nöthen; Per Hofmann; Peter S. Braund; Evanthia Mergia; Wibke Reinhard; Christof Burgdorf; Stefan Schreiber; Anthony J. Balmforth; Alistair S. Hall; Lars Bertram; Elisabeth Steinhagen-Thiessen; Shu Chen Li; Winfried März; Muredach Reilly; Sekar Kathiresan; Ruth McPherson; Ulrich Walter; Jurg Ott; Nilesh J. Samani; Tim M. Strom; Thomas Meitinger; Christian Hengstenberg; Heribert Schunkert

doi:10.1038/nature12722

Dysfunctional nitric oxide signalling increases risk of myocardial infarction

Jeanette Erdmann, Klaus Stark, Ulrike B. Esslinger, Philipp Moritz Rumpf, Doris Koesling, Cor DeWit, Frank J. Kaiser, Diana Braunholz, Anja Medack, Marcus Fischer, Martina E. Zimmermann, Stephanie Tennstedt, Elisabeth Graf, Sebastian Eck, Zouhair Aherrahrou, Janja Nahrstaedt, Christina Willenborg, Petra Bruse, Ingrid Brænne, Markus M. NöthenPer Hofmann, Peter S. Braund, Evanthia Mergia, Wibke Reinhard, Christof Burgdorf, Stefan Schreiber, Anthony J. Balmforth, Alistair S. Hall, Lars Bertram, Elisabeth Steinhagen-Thiessen, Shu Chen Li, Winfried März, Muredach Reilly, Sekar Kathiresan, Ruth McPherson, Ulrich Walter, Jurg Ott, Nilesh J. Samani, Tim M. Strom, Thomas Meitinger, Christian Hengstenberg, Heribert Schunkert^*

^*Korrespondierende/r Autor/-in für diese Arbeit

243 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Nature
Jahrgang	504
Ausgabenummer	7480
Seiten (von - bis)	432-436
Seitenumfang	5
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature12722
Publikationsstatus	Veröffentlicht - 12.11.2013

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Acknowledgements 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.Wöllner, U. Krabbe and J. Simon for technicalassistance.Furthermore, we would like to thank M. Becker, N. Buchholz, I. Demuth, R. Eckardt, H. Heekeren, U. Lindenberger, M. Lövdén, L. Müller, 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 WTCCC1 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 ‘Kardiovaskuläre Genomforschung’ and ‘Medizinische Genetik’ of the Universitätzu Lübeck, 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 UnitinCardiovascular Disease.U.W.issupported bythe BMBF(01EO1003).M.M.N. isa member of the DFG-funded Excellence Cluster ImmunoSensation.

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Erdmann, J., Stark, K., Esslinger, U. B., Rumpf, P. M., Koesling, D., DeWit, C., Kaiser, F. J., Braunholz, D., Medack, A., Fischer, M., Zimmermann, M. E., Tennstedt, S., Graf, E., Eck, S., Aherrahrou, Z., Nahrstaedt, J., Willenborg, C., Bruse, P., Brænne, I., ... Schunkert, H. (2013). Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature, 504(7480), 432-436. https://doi.org/10.1038/nature12722

@article{c9d83eaabcca4071b7a230b1882e60c8,

title = "Dysfunctional nitric oxide signalling increases risk of myocardial infarction",

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.",

author = "Jeanette Erdmann and Klaus Stark and Esslinger, \{Ulrike B.\} and Rumpf, \{Philipp Moritz\} and Doris Koesling and Cor DeWit and Kaiser, \{Frank J.\} and Diana Braunholz and Anja Medack and Marcus Fischer and Zimmermann, \{Martina E.\} and Stephanie Tennstedt and Elisabeth Graf and Sebastian Eck and Zouhair Aherrahrou and Janja Nahrstaedt and Christina Willenborg and Petra Bruse and Ingrid Br{\ae}nne and N{\"o}then, \{Markus M.\} and Per Hofmann and Braund, \{Peter S.\} and Evanthia Mergia and Wibke Reinhard and Christof Burgdorf and Stefan Schreiber and Balmforth, \{Anthony J.\} and Hall, \{Alistair S.\} and Lars Bertram and Elisabeth Steinhagen-Thiessen and Li, \{Shu Chen\} and Winfried M{\"a}rz and Muredach Reilly and Sekar Kathiresan and Ruth McPherson and Ulrich Walter and Jurg Ott and Samani, \{Nilesh J.\} and Strom, \{Tim M.\} and Thomas Meitinger and Christian Hengstenberg and Heribert Schunkert",

year = "2013",

month = nov,

day = "12",

doi = "10.1038/nature12722",

language = "English",

volume = "504",

pages = "432--436",

journal = "Nature",

issn = "0028-0836",

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number = "7480",

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Erdmann, J, Stark, K, Esslinger, UB, Rumpf, PM, Koesling, D, DeWit, C, Kaiser, FJ, Braunholz, D, Medack, A, Fischer, M, Zimmermann, ME, Tennstedt, S, Graf, E, Eck, S, Aherrahrou, Z, Nahrstaedt, J, Willenborg, C, Bruse, P, Brænne, I, Nöthen, MM, Hofmann, P, Braund, PS, Mergia, E, Reinhard, W, Burgdorf, C, Schreiber, S, Balmforth, AJ, Hall, AS, Bertram, L, Steinhagen-Thiessen, E, Li, SC, März, W, Reilly, M, Kathiresan, S, McPherson, R, Walter, U, Ott, J, Samani, NJ, Strom, TM, Meitinger, T, Hengstenberg, C & Schunkert, H 2013, 'Dysfunctional nitric oxide signalling increases risk of myocardial infarction', Nature, Jg. 504, Nr. 7480, S. 432-436. https://doi.org/10.1038/nature12722

TY - JOUR

T1 - Dysfunctional nitric oxide signalling increases risk of myocardial infarction

AU - Erdmann, Jeanette

AU - Stark, Klaus

AU - Esslinger, Ulrike B.

AU - Rumpf, Philipp Moritz

AU - Koesling, Doris

AU - DeWit, Cor

AU - Kaiser, Frank J.

AU - Braunholz, Diana

AU - Medack, Anja

AU - Fischer, Marcus

AU - Zimmermann, Martina E.

AU - Tennstedt, Stephanie

AU - Graf, Elisabeth

AU - Eck, Sebastian

AU - Aherrahrou, Zouhair

AU - Nahrstaedt, Janja

AU - Willenborg, Christina

AU - Bruse, Petra

AU - Brænne, Ingrid

AU - Nöthen, Markus M.

AU - Hofmann, Per

AU - Braund, Peter S.

AU - Mergia, Evanthia

AU - Reinhard, Wibke

AU - Burgdorf, Christof

AU - Schreiber, Stefan

AU - Balmforth, Anthony J.

AU - Hall, Alistair S.

AU - Bertram, Lars

AU - Steinhagen-Thiessen, Elisabeth

AU - Li, Shu Chen

AU - März, Winfried

AU - Reilly, Muredach

AU - Kathiresan, Sekar

AU - McPherson, Ruth

AU - Walter, Ulrich

AU - Ott, Jurg

AU - Samani, Nilesh J.

AU - Strom, Tim M.

AU - Meitinger, Thomas

AU - Hengstenberg, Christian

AU - Schunkert, Heribert

PY - 2013/11/12

Y1 - 2013/11/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84890557979

U2 - 10.1038/nature12722

DO - 10.1038/nature12722

M3 - Journal articles

C2 - 24213632

AN - SCOPUS:84890557979

SN - 0028-0836

VL - 504

SP - 432

EP - 436

JO - Nature

JF - Nature

IS - 7480

ER -

Dysfunctional nitric oxide signalling increases risk of myocardial infarction

Abstract

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