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Dysfunctional nitric oxide signalling increases risk of myocardial infarction.
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- Additional Information
- Corporate Authors:
- Source:
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
- Publication Information:
Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
- Subject Terms:
- Abstract:
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.
- Comments:
Comment in: Circ Cardiovasc Genet. 2014 Feb;7(1):93-4. (PMID: 24550432)
Comment in: Circ Res. 2014 Apr 25;114(9):1372-3. (PMID: 24763461)
- References:
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- Grant Information:
NF-SI-0611-10170 United Kingdom DH_ Department of Health; United Kingdom BHF_ British Heart Foundation
- Contributed Indexing:
Investigator: S Kathiresan; MP Reilly; NJ Samani; H Schunkert; J Erdmann; TL Assimes; E Boerwinkle; J Erdmann; A Hall; C Hengstenberg; S Kathiresan; IR König; R Laaksonen; R McPherson; MP Reilly; NJ Samani; H Schunkert; JR Thompson; U Thorsteinsdottir; A Ziegler; IR König; JR Thompson; D Absher; L Chen; L Cupples; E Halperin; M Li; K Musunuru; M Preuss; A Schillert; G Thorleifsson; BF Voight; GA Wells; D Absher; TL Assimes; S Fortmann; A Go; M Hlatky; C Iribarren; J Knowles; R Myers; T Quertermous; S Sidney; N Risch; H Tang; S Blankenberg; T Zeller; A Schillert; P Wild; A Ziegler; R Schnabel; C Sinning; K Lackner; L Tiret; V Nicaud; F Cambien; C Bickel; HJ Rupprecht; C Perret; C Proust; T Münzel; M Barbalic; J Bis; E Boerwinkle; IY Chen; L Cupples; A Dehghan; S Demissie-Banjaw; A Folsom; N Glazer; V Gudnason; T Harris; S Heckbert; D Levy; T Lumley; K Marciante; A Morrison; CJ O'Donnell; BM Psaty; K Rice; JI Rotter; DS Siscovick; N Smith; A Smith; KD Taylor; C van Duijn; K Volcik; J Whitteman; V Ramachandran; A Hofman; A Uitterlinden; S Gretarsdottir; JR Gulcher; H Holm; A Kong; K Stefansson; G Thorgeirsson; K Andersen; G Thorleifsson; U Thorsteinsdottir; J Erdmann; M Fischer; A Grosshennig; C Hengstenberg; IR König; W Lieb; P Linsel-Nitschke; M Preuss; K Stark; S Schreiber; HE Wichmann; A Ziegler; H Schunkert; Z Aherrahrou; P Bruse; A Doering; J Erdmann; C Hengstenberg; T Illig; N Klopp; IR König; P Diemert; C Loley; A Medack; C Meisinger; T Meitinger; J Nahrstedt; A Peters; M Preuss; K Stark; AK Wagner; HE Wichmann; C Willenborg; A Ziegler; H Schunkert; BO Böhm; H Dobnig; TB Grammer; E Halperin; MM Hoffmann; M Kleber; R Laaksonen; W März; A Meinitzer; BR Winkelmann; S Pilz; W Renner; H Scharnagl; T Stojakovic; A Tomaschitz; K Winkler; BF Voight; K Musunuru; C Guiducci; N Burtt; SB Gabriel; DS Siscovick; CJ O'Donnell; R Elosua; L Peltonen; V Salomaa; SM Schwartz; O Melander; D Altshuler; S Kathiresan; AF Stewart; L Chen; S Dandona; GA Wells; O Jarinova; R McPherson; R Roberts; MP Reilly; M Li; L Qu; R Wilensky; W Matthai; HH Hakonarson; J Devaney; MS Burnett; AD Pichard; KM Kent; L Satler; JM Lindsay; R Waksman; CW Knouff; DM Waterworth; MC Walker; V Mooser; SE Epstein; DJ Rader; NJ Samani; JR Thompson; PS Braund; CP Nelson; BJ Wright; AJ Balmforth; SG Ball; AS Hall
- Accession Number:
0 (CCT7 protein, human)
0 (GUCY1A2 protein, human)
0 (Gucy1a3 protein, mouse)
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)
- Publication Date:
Date Created: 20131112 Date Completed: 20140121 Latest Revision: 20220129
- Publication Date:
20221213
- Accession Number:
10.1038/nature12722
- Accession Number:
24213632
No Comments.