TY - JOUR
T1 - IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation
AU - Antl, Melanie
AU - Von Brühl, Marie Luise
AU - Eiglsperger, Christina
AU - Werner, Matthias
AU - Konrad, Ildiko
AU - Kocher, Thomas
AU - Wilm, Matthias
AU - Hofmann, Franz
AU - Massberg, Steffen
AU - Schlossmann, Jens
PY - 2007/1/15
Y1 - 2007/1/15
N2 - 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.
AB - 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.
U2 - 10.1182/blood-2005-10-026294
DO - 10.1182/blood-2005-10-026294
M3 - Article
SN - 0006-4971
VL - 109
SP - 552
EP - 559
JO - Blood
JF - Blood
IS - 2
ER -