IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation

Melanie Antl, Marie Luise Von Brühl, Christina Eiglsperger, Matthias Werner, Ildiko Konrad, Thomas Kocher, Matthias Wilm, Franz Hofmann, Steffen Massberg, Jens Schlossmann

    Research output: Contribution to journalArticlepeer-review


    Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke. A central regulatory pathway conveying inhibition of platelet activation/aggregation is nitric oxide (NO)/cyclic GMP (cGMP) signaling by cGMP-dependent protein kinase I (cGKI). However, the regulatory cascade downstream of cGKI mediating platelet inhibition is still unclear. Here, we show that the inositol-1,4,5-trisphosphate receptor-associated cGMP kinase substrate (IRAG) is abundantly expressed in platelets and assembled in a macrocomplex together with cGKIβ and the inositol-1,4,5-trisphosphate receptor type I (InsP 3RI). cGKI phosphorylates IRAG at Ser664 and Ser677 in intact platelets. Targeted deletion of the IRAG-InsP 3RI interaction in IRAG Δ12/Δ12 mutant mice leads to a loss of NO/cGMP-dependent inhibition of fibrinogen-receptor activation and platelet aggregation. Intracellular calcium transients were not affected by DEA/NO or cGMP in mutant platelets. Furthermore, intravital microscopy shows that NO fails to prevent arterial thrombosis of the injured carotid artery in IRAG Δ12/Δ12 mutants. These findings reveal that interaction between IRAG and InsP 3RI has a central role in NO/cGMP-dependent inhibition of platelet aggregation and in vivo thrombosis. © 2007 by The American Society of Hematology.
    Original languageEnglish
    Pages (from-to)552-559
    Number of pages7
    Issue number2
    Publication statusPublished - 15 Jan 2007


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