IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation.
Blood
; 109(2): 552-9, 2007 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-16990611
ABSTRACT
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 cGKIbeta and the inositol-1,4,5-trisphosphate receptor type I (InsP3RI). cGKI phosphorylates IRAG at Ser664 and Ser677 in intact platelets. Targeted deletion of the IRAG-InsP3RI interaction in IRAGDelta12/Delta12 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 IRAGDelta12/Delta12 mutants. These findings reveal that interaction between IRAG and InsP3RI has a central role in NO/cGMP-dependent inhibition of platelet aggregation and in vivo thrombosis.
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Banco de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
/
Trombosis
/
Transducción de Señal
/
Agregación Plaquetaria
/
GMP Cíclico
/
Proteínas de la Membrana
/
Óxido Nítrico
Límite:
Animals
/
Humans
Idioma:
En
Año:
2007
Tipo del documento:
Article