PortalPublikationenDysfunctional nitric oxide signalling increases risk of myoc...

Dysfunctional nitric oxide signalling increases risk of myocardial infarction

Standard

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

in: NATURE, Jahrgang 504, Nr. 7480, 19.12.2013, S. 432-436.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Erdmann, J, Stark, K, Esslinger, UB, Rumpf, PM, Koesling, D, de Wit, 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, S-C, März, W, Reilly, M, Kathiresan, S, McPherson, R, Walter, U, Ott, J, Samani, NJ, Strom, TM, Meitinger, T, Hengstenberg, C, Schunkert, H & CARDIoGRAM Consortium 2013, 'Dysfunctional nitric oxide signalling increases risk of myocardial infarction', NATURE, Jg. 504, Nr. 7480, S. 432-436. https://doi.org/10.1038/nature12722

APA

Erdmann, J., Stark, K., Esslinger, U. B., Rumpf, P. M., Koesling, D., de Wit, 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., ... CARDIoGRAM Consortium (2013). Dysfunctional nitric oxide signalling increases risk of myocardial infarction. NATURE, 504(7480), 432-436. https://doi.org/10.1038/nature12722

Vancouver

Erdmann J, Stark K, Esslinger UB, Rumpf PM, Koesling D, de Wit C et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction. NATURE. 2013 Dez 19;504(7480):432-436. https://doi.org/10.1038/nature12722

Bibtex

@article{8011380dc7a948df9364dca70babeafb,
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. ",
keywords = "Animals, Chaperonin Containing TCP-1/genetics, Cyclic GMP/metabolism, Disease Susceptibility/metabolism, Exome/genetics, Female, Genetic Predisposition to Disease, Guanylate Cyclase/deficiency, HEK293 Cells, Humans, Male, Mice, Mutation/genetics, Myocardial Infarction/genetics, Nitric Oxide/metabolism, Pedigree, Platelet Activation, Receptors, Cytoplasmic and Nuclear/deficiency, Reproducibility of Results, Signal Transduction, Solubility, Soluble Guanylyl Cyclase, Thrombosis/metabolism, Vasodilation",
author = "Jeanette Erdmann and Klaus Stark and Esslinger, {Ulrike B} and Rumpf, {Philipp Moritz} and Doris Koesling and {de Wit}, Cor 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 Shu-Chen Li 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 and {CARDIoGRAM Consortium} and Tanja Zeller and Stefan Blankenberg",
year = "2013",
month = dec,
day = "19",
doi = "10.1038/nature12722",
language = "English",
volume = "504",
pages = "432--436",
journal = "NATURE",
issn = "0028-0836",
publisher = "NATURE PUBLISHING GROUP",
number = "7480",

}

RIS

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 - de Wit, 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

AU - CARDIoGRAM Consortium

AU - Zeller, Tanja

AU - Blankenberg, Stefan

PY - 2013/12/19

Y1 - 2013/12/19

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.

KW - Animals

KW - Chaperonin Containing TCP-1/genetics

KW - Cyclic GMP/metabolism

KW - Disease Susceptibility/metabolism

KW - Exome/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Guanylate Cyclase/deficiency

KW - HEK293 Cells

KW - Humans

KW - Male

KW - Mice

KW - Mutation/genetics

KW - Myocardial Infarction/genetics

KW - Nitric Oxide/metabolism

KW - Pedigree

KW - Platelet Activation

KW - Receptors, Cytoplasmic and Nuclear/deficiency

KW - Reproducibility of Results

KW - Signal Transduction

KW - Solubility

KW - Soluble Guanylyl Cyclase

KW - Thrombosis/metabolism

KW - Vasodilation

U2 - 10.1038/nature12722

DO - 10.1038/nature12722

M3 - SCORING: Journal article

C2 - 24213632

VL - 504

SP - 432

EP - 436

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7480

ER -