Dysfunctional nitric oxide signalling increases risk of myocardial infarction.


Serval ID
Article: article from journal or magazin.
Dysfunctional nitric oxide signalling increases risk of myocardial infarction.
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., Nöthen M.M., Hofmann P., Braund P.S., Mergia E., Reinhard W., Burgdorf C., Schreiber S., Balmforth A.J., Hall A.S., Bertram L., Steinhagen-Thiessen E., Li S.C., März W., Reilly M., Kathiresan S., McPherson R., Walter U., CARDIoGRAM , Ott J., Ott J., Samani N.J., Strom T.M., Meitinger T., Hengstenberg C., Schunkert H.
CARDIoGRAM , Kathiresan S., Reilly MP., Samani NJ., Schunkert H., Erdmann J., Assimes TL., Boerwinkle E., Erdmann J., Hall A., Hengstenberg C., Kathiresan S., König IR., Laaksonen R., McPherson R., Reilly MP., Samani NJ., Schunkert H., Thompson JR., Thorsteinsdottir U., Ziegler A., König IR., Thompson JR., Absher D., Chen L., Cupples L., Halperin E., Li M., Musunuru K., Preuss M., Schillert A., Thorleifsson G., Voight BF., Wells GA., Absher D., Assimes TL., Fortmann S., Go A., Hlatky M., Iribarren C., Knowles J., Myers R., Quertermous T., Sidney S., Risch N., Tang H., Blankenberg S., Zeller T., Schillert A., Wild P., Ziegler A., Schnabel R., Sinning C., Lackner K., Tiret L., Nicaud V., Cambien F., Bickel C., Rupprecht HJ., Perret C., Proust C., Münzel T., Barbalic M., Bis J., Boerwinkle E., Chen IY., Cupples L., Dehghan A., Demissie-Banjaw S., Folsom A., Glazer N., Gudnason V., Harris T., Heckbert S., Levy D., Lumley T., Marciante K., Morrison A., O'Donnell CJ., Psaty BM., Rice K., Rotter JI., Siscovick DS., Smith N., Smith A., Taylor KD., van Duijn C., Volcik K., Whitteman J., Ramachandran V., Hofman A., Uitterlinden A., Gretarsdottir S., Gulcher JR., Holm H., Kong A., Stefansson K., Thorgeirsson G., Andersen K., Thorleifsson G., Thorsteinsdottir U., Erdmann J., Fischer M., Grosshennig A., Hengstenberg C., König IR., Lieb W., Linsel-Nitschke P., Preuss M., Stark K., Schreiber S., Wichmann HE., Ziegler A., Schunkert H., Aherrahrou Z., Bruse P., Doering A., Erdmann J., Hengstenberg C., Illig T., Klopp N., König IR., Diemert P., Loley C., Medack A., Meisinger C., Meitinger T., Nahrstedt J., Peters A., Preuss M., Stark K., Wagner AK., Wichmann HE., Willenborg C., Ziegler A., Schunkert H., Böhm BO., Dobnig H., Grammer TB., Halperin E., Hoffmann MM., Kleber M., Laaksonen R., März W., Meinitzer A., Winkelmann BR., Pilz S., Renner W., Scharnagl H., Stojakovic T., Tomaschitz A., Winkler K., Voight BF., Musunuru K., Guiducci C., Burtt N., Gabriel SB., Siscovick DS., O'Donnell CJ., Elosua R., Peltonen L., Salomaa V., Schwartz SM., Melander O., Altshuler D., Kathiresan S., Stewart AF., Chen L., Dandona S., Wells GA., Jarinova O., McPherson R., Roberts R., Reilly MP., Li M., Qu L., Wilensky R., Matthai W., Hakonarson HH., Devaney J., Burnett MS., Pichard AD., Kent KM., Satler L., Lindsay JM., Waksman R., Knouff CW., Waterworth DM., Walker MC., Mooser V., Epstein SE., Rader DJ., Samani NJ., Thompson JR., Braund PS., Nelson CP., Wright BJ., Balmforth AJ., Ball SG., Hall AS.
1476-4687 (Electronic)
Publication state
Issued date
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Animals, Chaperonin Containing TCP-1/genetics, Chaperonin Containing TCP-1/metabolism, Cyclic GMP/metabolism, Disease Susceptibility/metabolism, Exome/genetics, Female, Genetic Predisposition to Disease, Guanylate Cyclase/deficiency, Guanylate Cyclase/genetics, HEK293 Cells, Humans, Male, Mice, Mutation/genetics, Myocardial Infarction/genetics, Myocardial Infarction/metabolism, Nitric Oxide/metabolism, Pedigree, Platelet Activation, Receptors, Cytoplasmic and Nuclear/deficiency, Receptors, Cytoplasmic and Nuclear/genetics, Reproducibility of Results, Signal Transduction, Solubility, Thrombosis/metabolism, Vasodilation
Create date
10/10/2014 11:44
Last modification date
20/08/2019 16:03
Usage data