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
N1 - Funding Information:
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.
PY - 2013/11/10
Y1 - 2013/11/10
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 - http://www.scopus.com/inward/record.url?scp=84890557979&partnerID=8YFLogxK
U2 - 10.1038/nature12722
DO - 10.1038/nature12722
M3 - Article
C2 - 24213632
AN - SCOPUS:84890557979
SN - 0028-0836
VL - 504
SP - 432
EP - 436
JO - Nature
JF - Nature
IS - 7480
ER -