Rac1-mediated signaling plays a central role in secretion-dependent platelet aggregation in human blood stimulated by atherosclerotic plaque.
J Transl Med
; 8: 128, 2010 Dec 06.
Article
en En
| MEDLINE
| ID: mdl-21134286
ABSTRACT
BACKGROUND:
Platelet activation requires rapid remodeling of the actin cytoskeleton which is regulated by small GTP-binding proteins. By using the Rac1-specific inhibitor NSC23766, we have recently found that Rac1 is a central component of a signaling pathway that regulates dephosphorylation and activation of the actin-dynamising protein cofilin, dense and α-granule secretion, and subsequent aggregation of thrombin-stimulated washed platelets.OBJECTIVES:
To study whether NSC23766 inhibits stimulus-induced platelet secretion and aggregation in blood.METHODS:
Human platelet aggregation and ATP-secretion were measured in hirudin-anticoagulated blood and platelet-rich plasma (PRP) by using multiple electrode aggregometry and the Lumi-aggregometer. Platelet P-selectin expression was quantified by flow cytometry.RESULTS:
NSC23766 (300 µM) inhibited TRAP-, collagen-, atherosclerotic plaque-, and ADP-induced platelet aggregation in blood by 95.1%, 93.4%, 92.6%, and 70%, respectively. The IC50 values for inhibition of TRAP-, collagen-, and atherosclerotic plaque-, were 50 ± 18 µM, 64 ± 35 µM, and 50 ± 30 µM NSC23766 (mean ± SD, n = 3-7), respectively. In blood containing RGDS to block integrin αIIbß3-mediated platelet aggregation, NSC23766 (300 µM) completely inhibited P-selectin expression and reduced ATP-secretion after TRAP and collagen stimulation by 73% and 85%, respectively. In ADP-stimulated PRP, NSC23766 almost completely inhibited P-selectin expression, in contrast to aspirin, which was ineffective. Moreover, NSC23766 (300 µM) decreased plaque-stimulated platelet adhesion/aggregate formation under arterial flow conditions (1500s-1) by 72%.CONCLUSIONS:
Rac1-mediated signaling plays a central role in secretion-dependent platelet aggregation in blood stimulated by a wide array of platelet agonists including atherosclerotic plaque. By specifically inhibiting platelet secretion, the pharmacological targeting of Rac1 could be an interesting approach in the development of future antiplatelet drugs.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Adenosina Trifosfato
/
Agregación Plaquetaria
/
Proteína de Unión al GTP rac1
/
Placa Aterosclerótica
Límite:
Humans
Idioma:
En
Revista:
J Transl Med
Año:
2010
Tipo del documento:
Article
País de afiliación:
Alemania