Document Detail


Dysfunctional nitric oxide signalling increases risk of myocardial infarction.
MedLine Citation:
PMID:  24213632     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jeanette Erdmann; Klaus Stark; Ulrike B Esslinger; Philipp Moritz Rumpf; Doris Koesling; Cor de Wit; Frank J Kaiser; Diana Braunholz; Anja Medack; Marcus Fischer; Martina E Zimmermann; Stephanie Tennstedt; Elisabeth Graf; Sebastian Eck; Zouhair Aherrahrou; Janja Nahrstaedt; Christina Willenborg; Petra Bruse; Ingrid Brænne; Markus M Nöthen; Per Hofmann; Peter S Braund; Evanthia Mergia; Wibke Reinhard; Christof Burgdorf; Stefan Schreiber; Anthony J Balmforth; Alistair S Hall; Lars Bertram; Elisabeth Steinhagen-Thiessen; Shu-Chen Li; Winfried März; Muredach Reilly; Sekar Kathiresan; Ruth McPherson; Ulrich Walter; ; Jurg Ott; Nilesh J Samani; Tim M Strom; Thomas Meitinger; Christian Hengstenberg; Heribert Schunkert
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-11-10
Journal Detail:
Title:  Nature     Volume:  504     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2013 Dec 
Date Detail:
Created Date:  2013-12-19     Completed Date:  2014-01-21     Revised Date:  2014-05-30    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  432-6     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Chaperonin Containing TCP-1 / genetics,  metabolism
Cyclic GMP / metabolism
Disease Susceptibility / metabolism*
Exome / genetics
Female
Genetic Predisposition to Disease
Guanylate Cyclase / deficiency,  genetics,  metabolism
HEK293 Cells
Humans
Male
Mice
Mutation / genetics
Myocardial Infarction / genetics,  metabolism*,  physiopathology
Nitric Oxide / metabolism*
Pedigree
Platelet Activation
Receptors, Cytoplasmic and Nuclear / deficiency,  genetics,  metabolism
Reproducibility of Results
Signal Transduction*
Solubility
Thrombosis / metabolism
Vasodilation
Grant Support
ID/Acronym/Agency:
//British Heart Foundation
Chemical
Reg. No./Substance:
0/CCT7 protein, human; 0/Receptors, Cytoplasmic and Nuclear; 31C4KY9ESH/Nitric Oxide; EC 3.6.1.-/Chaperonin Containing TCP-1; EC 4.6.1.2/Guanylate Cyclase; EC 4.6.1.2/soluble guanylyl cyclase; H2D2X058MU/Cyclic GMP
Investigator
Investigator/Affiliation:
Sekar Kathiresan / ; Muredach P Reilly / ; Nilesh J Samani / ; Heribert Schunkert / ; Jeanette Erdmann / ; Themistocles L Assimes / ; Eric Boerwinkle / ; Jeanette Erdmann / ; Alistair Hall / ; Christian Hengstenberg / ; Sekar Kathiresan / ; Inke R König / ; Reijo Laaksonen / ; Ruth McPherson / ; Muredach P Reilly / ; Nilesh J Samani / ; Heribert Schunkert / ; John R Thompson / ; Unnur Thorsteinsdottir / ; Andreas Ziegler / ; Inke R König / ; John R Thompson / ; Devin Absher / ; Li Chen / ; L Adrienne Cupples / ; Eran Halperin / ; Mingyao Li / ; Kiran Musunuru / ; Michael Preuss / ; Arne Schillert / ; Gudmar Thorleifsson / ; Benjamin F Voight / ; George A Wells / ; Devin Absher / ; Themistocles L Assimes / ; Stephen Fortmann / ; Alan Go / ; Mark Hlatky / ; Carlos Iribarren / ; Joshua Knowles / ; Richard Myers / ; Thomas Quertermous / ; Steven Sidney / ; Neil Risch / ; Hua Tang / ; Stefan Blankenberg / ; Tanja Zeller / ; Arne Schillert / ; Philipp Wild / ; Andreas Ziegler / ; Renate Schnabel / ; Christoph Sinning / ; Karl Lackner / ; Laurence Tiret / ; Viviane Nicaud / ; Francois Cambien / ; Christoph Bickel / ; Hans J Rupprecht / ; Claire Perret / ; Carole Proust / ; Thomas Münzel / ; Maja Barbalic / ; Joshua Bis / ; Eric Boerwinkle / ; Ida Yii-Der Chen / ; L Adrienne Cupples / ; Abbas Dehghan / ; Serkalem Demissie-Banjaw / ; Aaron Folsom / ; Nicole Glazer / ; Vilmundur Gudnason / ; Tamara Harris / ; Susan Heckbert / ; Daniel Levy / ; Thomas Lumley / ; Kristin Marciante / ; Alanna Morrison / ; Christopher J O'Donnell / ; Bruce M Psaty / ; Kenneth Rice / ; Jerome I Rotter / ; David S Siscovick / ; Nicholas Smith / ; Albert Smith / ; Kent D Taylor / ; Cornelia van Duijn / ; Kelly Volcik / ; Jaqueline Whitteman / ; Vasan Ramachandran / ; Albert Hofman / ; Andre Uitterlinden / ; Solveig Gretarsdottir / ; Jeffrey R Gulcher / ; Hilma Holm / ; Augustine Kong / ; Kari Stefansson / ; Gudmundur Thorgeirsson / ; Karl Andersen / ; Gudmar Thorleifsson / ; Unnur Thorsteinsdottir / ; Jeanette Erdmann / ; Marcus Fischer / ; Anika Grosshennig / ; Christian Hengstenberg / ; Inke R König / ; Wolfgang Lieb / ; Patrick Linsel-Nitschke / ; Michael Preuss / ; Klaus Stark / ; Stefan Schreiber / ; H-Erich Wichmann / ; Andreas Ziegler / ; Heribert Schunkert / ; Zouhair Aherrahrou / ; Petra Bruse / ; Angela Doering / ; Jeanette Erdmann / ; Christian Hengstenberg / ; Thomas Illig / ; Norman Klopp / ; Inke R König / ; Patrick Diemert / ; Christina Loley / ; Anja Medack / ; Christina Meisinger / ; Thomas Meitinger / ; Janja Nahrstedt / ; Annette Peters / ; Michael Preuss / ; Klaus Stark / ; Arnika K Wagner / ; H-Erich Wichmann / ; Christina Willenborg / ; Andreas Ziegler / ; Heribert Schunkert / ; Bernhard O Böhm / ; Harald Dobnig / ; Tanja B Grammer / ; Eran Halperin / ; Michael M Hoffmann / ; Marcus Kleber / ; Reijo Laaksonen / ; Winfried März / ; Andreas Meinitzer / ; Bernhard R Winkelmann / ; Stefan Pilz / ; Wilfried Renner / ; Hubert Scharnagl / ; Tatjana Stojakovic / ; Andreas Tomaschitz / ; Karl Winkler / ; Benjamin F Voight / ; Kiran Musunuru / ; Candace Guiducci / ; Noel Burtt / ; Stacey B Gabriel / ; David S Siscovick / ; Christopher J O'Donnell / ; Roberto Elosua / ; Leena Peltonen / ; Veikko Salomaa / ; Stephen M Schwartz / ; Olle Melander / ; David Altshuler / ; Sekar Kathiresan / ; Alexandre F R Stewart / ; Li Chen / ; Sonny Dandona / ; George A Wells / ; Olga Jarinova / ; Ruth McPherson / ; Robert Roberts / ; Muredach P Reilly / ; Mingyao Li / ; Liming Qu / ; Robert Wilensky / ; William Matthai / ; Hakon H Hakonarson / ; Joe Devaney / ; Mary Susan Burnett / ; Augusto D Pichard / ; Kenneth M Kent / ; Lowell Satler / ; Joseph M Lindsay / ; Ron Waksman / ; Christopher W Knouff / ; Dawn M Waterworth / ; Max C Walker / ; Vincent Mooser / ; Stephen E Epstein / ; Daniel J Rader / ; Nilesh J Samani / ; John R Thompson / ; Peter S Braund / ; Christopher P Nelson / ; Benjamin J Wright / ; Anthony J Balmforth / ; Stephen G Ball / ; Alistair S Hall /
Comments/Corrections
Comment In:
Circ Cardiovasc Genet. 2014 Feb;7(1):93-4   [PMID:  24550432 ]
Circ Res. 2014 Apr 25;114(9):1372-3   [PMID:  24763461 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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