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Dysfunctional nitric oxide signalling increases risk of myocardial infarction

Nature volume 504, pages 432–436 (2013)Cite this article

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Abstract

Myocardial infarction, a leading cause of death in the Western world1, 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 artery2. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history3. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification4. 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)5, and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex6, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation7. 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.

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Figure 1: Pedigree of the extended MI family with several individuals suffering from myocardial infarctions.
Figure 2: Reduced expression and enzymatic activity of the identified sGC mutants in HEK 293 cells.
Figure 3: CCTη is required for sGC expression and function.
Figure 4: Reduced sGC expression and activity in platelets of double-mutation carriers.
Figure 5: Thrombus formation in-vivo in mice deficient for the α1-sGC (α1−/−).

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Data deposits

Variant data is available in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) with accession numbers SCV000083870 for NM_001130683.2:c.488dup and SCV000083871 for NM_001166284.1:c.1313C>T.

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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 technical assistance. 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 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 ‘Kardiovaskuläre Genomforschung’ and ‘Medizinische Genetik’ of the Universität zu 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 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.

Author information

Author notes

  1. Jeanette Erdmann, Klaus Stark, Ulrike B. Esslinger and Philipp Moritz Rumpf: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany ,

    Jeanette Erdmann, Anja Medack, Stephanie Tennstedt, Zouhair Aherrahrou, Janja Nahrstaedt, Christina Willenborg, Petra Bruse & Ingrid Brænne

  2. German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany ,

    Jeanette Erdmann, Cor de Wit, Frank J. Kaiser, Zouhair Aherrahrou & Christina Willenborg

  3. Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany ,

    Klaus Stark, Ulrike B. Esslinger, Marcus Fischer & Martina E. Zimmermann

  4. Department of Genetic Epidemiology, University of Regensburg, 93053 Regensburg, Germany,

    Klaus Stark

  5. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S937 Paris, France ,

    Ulrike B. Esslinger

  6. Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany ,

    Philipp Moritz Rumpf, Wibke Reinhard, Christof Burgdorf, Thomas Meitinger, Christian Hengstenberg & Heribert Schunkert

  7. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany ,

    Philipp Moritz Rumpf, Wibke Reinhard, Christian Hengstenberg & Heribert Schunkert

  8. Department of Pharmacology and Toxicology, Ruhr-University Bochum, 44801 Bochum, Germany,

    Doris Koesling & Evanthia Mergia

  9. Institut für Physiologie, Universität zu Lübeck, 23562 Lübeck, Germany ,

    Cor de Wit

  10. Institut für Humangenetik, Universität zu Lübeck, 23562 Lübeck, Germany ,

    Frank J. Kaiser & Diana Braunholz

  11. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany ,

    Elisabeth Graf, Sebastian Eck, Tim M. Strom & Thomas Meitinger

  12. Institute of Human Genetics, Technische Universität München, 81675 München, Germany ,

    Elisabeth Graf, Sebastian Eck, Tim M. Strom & Thomas Meitinger

  13. Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany ,

    Markus M. Nöthen & Per Hofmann

  14. Department of Genomics, Research Center Life & Brain, University of Bonn, 53127 Bonn, Germany,

    Markus M. Nöthen

  15. Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, 4003 Basel, Switzerland,

    Per Hofmann

  16. Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK,

    Peter S. Braund & Nilesh J. Samani

  17. Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE1 7RH, UK ,

    Peter S. Braund & Nilesh J. Samani

  18. Institute of Clinical Molecular Biology, Christian-Albrecht-Universität, 24105 Kiel, Germany ,

    Stefan Schreiber

  19. Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK,

    Anthony J. Balmforth

  20. Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK,

    Alistair S. Hall

  21. Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany,

    Lars Bertram

  22. Charité Research Group on Geriatrics, Charité-Universitätsmedizin, 10117 Berlin, Germany ,

    Elisabeth Steinhagen-Thiessen

  23. Center for Lifespan Psychology, Max Planck Institute for Human Development, 14195 Berlin, Germany ,

    Shu-Chen Li

  24. Department of Psychology, TU Dresden, 01062 Dresden, Germany,

    Shu-Chen Li

  25. Synlab Academy and Business Development, synlab Services GmbH, 68165 Mannheim, Germany ,

    Winfried März

  26. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria ,

    Winfried März

  27. Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany ,

    Winfried März

  28. The Cardiovascular Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Muredach Reilly

  29. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, 02215, Massachusetts, USA

    Sekar Kathiresan

  30. Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02215, Massachusetts, USA

    Sekar Kathiresan

  31. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, 02215, Massachusetts, USA

    Sekar Kathiresan

  32. University of Ottawa, Heart Institute, Ottawa, Ontario K1Y 4W7, Canada ,

    Ruth McPherson

  33. Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin Mainz, 55131 Mainz, Germany ,

    Ulrich Walter

  34. German Centre for Cardiovascular Research (DZHK), partner site RheinMain, 55131 Mainz, Germany ,

    Ulrich Walter

  35. Institute of Psychology, Chinese Academy of Sciences, Beijing, 100864, China

    Jurg Ott

  36. Laboratory of Statistical Genetics, Rockefeller University, 10065, New York, USA

    Jurg Ott

Authors
  1. Jeanette Erdmann
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  2. Klaus Stark
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Consortia

CARDIoGRAM

Contributions

J.E., C.H., F.J.K., T.M., N.J.S., H.S. and K.S. designed the study. Z.A., D.B., P.B., C.d.W., S.E., U.B.E., E.G., F.J.K., D.K., A.M., E.M., W.R., P.M.R., T.M.S. and M.E.Z. conducted the experiments. I.B., M.F., J.N., J.O., K.S., T.M.S., S.T. and C.W. analysed the data. A.J.B., L.B., P.S.B., C.B., A.S.H., P.H., S.K., S.-C.L., W.M., R.M., T.M., M.M.N., M.R., N.J.S., S.S., E.S.-T. and U.W. provided material, data and analysis tools. J.E., C.d.W., C.H., F.J.K., N.J.S. and H.S. wrote the paper. C.H. and H.S. contributed equally. See Supplementary Information for Members of CARDIoGRAM.

Corresponding authors

Correspondence to Jeanette Erdmann or Christian Hengstenberg.

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The authors declare no competing financial interests.

Additional information

A list of authors and their affiliations appears in the Supplementary Information.

Supplementary information

Supplementary Information

This file contains Supplementary Materials and Methods, Supplementary Tables 1-7, Supplementary Figures 1-8 and funding and affiliation details for CARDIoGRAM. (PDF 3117 kb)

Thrombus formation in arterioles in vivo

An arteriole in cremaster-microcirculation with a diameter of about 40 µm. Blood flow is from bottom to top, the animal has received high molecular weight FITC-dextran intravenously which is photoexcited by illuminating the preparation at 450-490nm using mercury lamp at time point 01:07:00. This is visible as a light spot in arteriole, which reflects the excitation of the dye. Thrombus formation starts to be visible downstream of the excitated area in the upper right corner 42 s later. Thereafter, flow decelerates and comes to complete stop 88 s after starting the photoexcitation, which is turned-off at this point. (AVI 7116 kb)

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Erdmann, J., Stark, K., Esslinger, U. et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature 504, 432–436 (2013). https://doi.org/10.1038/nature12722

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