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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Dysfunctional nitric oxide signalling increases risk of myocardial infarction.
Nature 504, 432-436 (2013)
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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Times Cited
Scopus
Cited By
Cited By
Altmetric
38.597
8.580
183
198
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern
Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Coronary-artery-disease ; Soluble Guanylate-cyclase ; Genome-wide Association ; Susceptibility Loci ; Adults
Sprache
englisch
Veröffentlichungsjahr
2013
HGF-Berichtsjahr
2013
ISSN (print) / ISBN
0028-0836
e-ISSN
1476-4687
Zeitschrift
Nature
Quellenangaben
Band: 504,
Heft: 7480,
Seiten: 432-436
Verlag
Nature Publishing Group
Verlagsort
London
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Human Genetics (IHG)
Institute of Epidemiology (EPI)
Research Unit Molecular Epidemiology (AME)
Institute of Epidemiology (EPI)
Research Unit Molecular Epidemiology (AME)
POF Topic(s)
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30503 - Chronic Diseases of the Lung and Allergies
30202 - Environmental Health
30503 - Chronic Diseases of the Lung and Allergies
30202 - Environmental Health
Forschungsfeld(er)
Genetics and Epidemiology
PSP-Element(e)
G-500700-001
G-503900-001
G-504200-001
G-504000-002
G-504000-006
G-503900-001
G-504200-001
G-504000-002
G-504000-006
PubMed ID
24213632
WOS ID
WOS:000328575300051
Scopus ID
84890557979
Erfassungsdatum
2013-11-13