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Alterations in the nitric oxide / soluble guanylyl cyclase pathway enhance the risk of myocardial infarction
Author(s) -
Wit Cor,
Kaiser Frank,
Aherrahrou Zouhair,
Koesling Doris,
Schunkert Heribert,
Erdmann Jeanette
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.686.10
Subject(s) - soluble guanylyl cyclase , nitric oxide , thrombus , transfection , hek 293 cells , myocardial infarction , medicine , chemistry , gene , guanylate cyclase , biochemistry , receptor
Myocardial infarction (MI) results from sudden atherothrombotic occlusion of a coronary artery, exhibits a genetic predisposition and clusters in families. We performed whole exome sequencing and analysed identified targets. In a MI family, heterozygous mutations in two functionally related genes, GUCY1A3 , encoding the α 1 ‐subunit of the soluble guanylyl cyclase (α 1 ‐sGC), and CCT7 , encoding a chaperonin containing TCP‐1 complex (CCT) protein, segregate with the disease. All family members with the GUCY1A3 (p.Leu163Phefs*24) and the CCT7 mutation (p.Ser525Leu) were affected. Transfection of sGC in HEK cells yielded its expression and NO‐induced cGMP formation, but transfection of the GUCY1A3 mutation was ineffective. Downregulation of CCT7 in VSM decreased sGC expression verifying the importance of CCT7 herein. In platelets of affected probands α 1 ‐sGC and NO‐induced cGMP formation was strongly reduced. Light‐dye induced thrombus formation in arterioles revealed the functional relevance of α 1 ‐sGC. Time to occlusion was shorter in α 1 ‐sGC deficient mice. Inhibition of endogenous NO accelerated thrombus formation only in wildtype and abrogated differences between genotypes indicating an absent inhibitory effect of NO in α 1 ‐sGC−/− mice. In conclusion, dysfunctional NO/sGC signalling may lead to premature MI and α 1 ‐sGC is decisive in continuous inhibition of thrombus formation thereby preventing MI.