IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation.
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IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation. / Antl, Melanie; von Brühl, Marie-Luise; Eiglsperger, Christina; Werner, Mathias; Konrad, Ildiko; Kocher, Thomas; Wilm, Matthias; Hofmann, Franz; Massberg, Steffen; Schlossmann, Jens.
in: BLOOD, Jahrgang 109, Nr. 2, 2, 2007, S. 552-559.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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, Mathias
AU - Konrad, Ildiko
AU - Kocher, Thomas
AU - Wilm, Matthias
AU - Hofmann, Franz
AU - Massberg, Steffen
AU - Schlossmann, Jens
PY - 2007
Y1 - 2007
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 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.
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 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 109
SP - 552
EP - 559
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 2
M1 - 2
ER -
