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Dysfunctional nitric oxide signalling increases risk of myocardial infarction.

TitleDysfunctional nitric oxide signalling increases risk of myocardial infarction.
Publication TypeJournal Article
Year of Publication2013
AuthorsErdmann J, Stark K, Esslinger UB, Rumpf PMoritz, 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
Secondary AuthorsSchunkert H
Corporate AuthorsCARDIOGRAM
Date Published2013 Dec 19
KeywordsAnimals, Chaperonin Containing TCP-1, Cyclic GMP, Disease Susceptibility, Exome, Female, Genetic Predisposition to Disease, Guanylate Cyclase, HEK293 Cells, Humans, Male, Mice, Mutation, Myocardial Infarction, Nitric Oxide, Pedigree, Platelet Activation, Receptors, Cytoplasmic and Nuclear, Reproducibility of Results, Signal Transduction, Solubility, Soluble Guanylyl Cyclase, Thrombosis, Vasodilation

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.

Alternate JournalNature
PubMed ID24213632
Grant ListNF-SI-0611-10170 / / Department of Health / United Kingdom
/ / British Heart Foundation / United Kingdom