Erdmann, Jeanette and Stark, Klaus and Esslinger, Ulrike B. and Rumpf, Philipp Moritz and Koesling, Doris and de Wit, Cor and Kaiser, Frank J. and Braunholz, Diana and Medack, Anja and Fischer, Marcus and Zimmermann, Martina E. and Tennstedt, Stephanie and Graf, Elisabeth and Eck, Sebastian and Aherrahrou, Zouhair and Nahrstaedt, Janja and Willenborg, Christina and Bruse, Petra and Braenne, Ingrid and Noethen, Markus M. and Hofmann, Per and Braund, Peter S. and Mergia, Evanthia and Reinhard, Wibke and Burgdorf, Christof and Schreiber, Stefan and Balmforth, Anthony J. and Hall, Alistair S. and Bertram, Lars and Steinhagen-Thiessen, Elisabeth and Li, Shu-Chen and Maerz, Winfried and Reilly, Muredach and Kathiresan, Sekar and McPherson, Ruth and Walter, Ulrich and Ott, Jurg and Samani, Nilesh J. and Strom, Tim M. and Meitinger, Thomas and Hengstenberg, Christian and Schunkert, Heribert (2013) Dysfunctional nitric oxide signalling increases risk of myocardial infarction. NATURE, 504 (7480). 432-+. ISSN 0028-0836, 1476-4687
Full text not available from this repository. (Request a copy)Abstract
Myocardial infarction, a leading cause of death intheWesternworld(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). Nextgeneration 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 relatedgenes, GUCY1A3 (p.Leu163Phefs*24) andCCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the alpha 1 subunit of soluble guanylyl cyclase (alpha 1-sGC)(5), and CCT7 encodes CCT eta, 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). Wedemonstratein vitro that mutations inbothGUCY1A3 and CCT7 severely reduce alpha 1-sGC as well as beta 1-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-oxideinduced cGMP formation. Mice deficient in alpha 1-sGC protein displayed accelerated thrombus formation in themicrocirculation 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SOLUBLE GUANYLATE-CYCLASE; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; DISEASE; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Mar 2020 13:06 |
| Last Modified: | 24 Mar 2020 13:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15514 |
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