Dysfunctional nitric oxide signalling increases risk of myocardial infarction

• Published in: Nature (London) Vol. 504; no. 7480; pp. 432 - 436
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2013; Nature Publishing Group
• Subjects: 13/1; 13/44; 45/23; 45/43; 631/208/2489/144; Animals; Blood clots; Cardiovascular disease; Chaperonin Containing TCP-1 - genetics; Chaperonin Containing TCP-1 - metabolism; Cyclic GMP - metabolism; Disease Susceptibility - metabolism; Exome - genetics; Female; Gene mutations; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic research; Genetics; Genomes; Guanylate Cyclase - deficiency; Guanylate Cyclase - genetics; Guanylate Cyclase - metabolism; Health aspects; Heart attack; HEK293 Cells; Humanities and Social Sciences; Humans; letter; Male; Mice; Mortality; multidisciplinary; Mutation; Mutation - genetics; Myocardial infarction; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Nitric oxide; Nitric Oxide - metabolism; Pedigree; Platelet Activation; Proteins; Receptors, Cytoplasmic and Nuclear - deficiency; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Reproducibility of Results; Risk factors; Science; Signal Transduction; Solubility; Soluble Guanylyl Cyclase; Thrombosis - metabolism; Vasodilation; Germany
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12722

Two private, heterozygous mutations in two functionally related genes,
GUCY1A3
and
CCT7
, are identified in an extended family with myocardial infarction; these genes encode proteins that work together to inhibit platelet activation after nitric oxide stimulation, suggesting a link between impaired nitric oxide signalling and myocardial infarction risk.
Signal failure raises cardiac disease risk
Next-generation sequencing in families with multiple affected individuals has revolutionized the identification of rare and private (single family or limited group) mutations. Here, the authors identify two private, heterozygous mutations in two functionally related genes,
GUCY1A3
and
CCT7
, in an extended family with myocardial infarction. The products of these genes work together to induce vasodilation and inhibit platelet activation upon stimulation with nitric oxide. Starting with a severely affected family, this work identifies a link between impaired nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversal of this signalling defect may provide a new therapeutic strategy for reducing the risk of myocardial infarction.
Myocardial infarction, a leading cause of death in the Western world
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
. Next-generation 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 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 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
. 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.