| Autor: |
Naik, Meghna U., Patel, Pravin, Derstine, Randall, Turaga, Ramya, Chen, Xi, Golla, Kalyan, Neeves, Keith B., Ichijo, Hidenori, Naik, Ulhas P. |
| Zdroj: |
Blood; March 2017, Vol. 129 Issue: 9 p1197-1209, 13p |
| Abstrakt: |
Mitogen-activated protein kinases (MAPKs) are expressed in platelets and are activated downstream of physiological agonists. Pharmacological and genetic evidence indicate that MAPKs play a significant role in hemostasis and thrombosis, but it is not well understood how MAPKs are activated upon platelet stimulation. Here, we show that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP3K family, is expressed in both human and murine platelets. ASK1 is rapidly and robustly activated upon platelet stimulation by physiological agonists. Disruption of Ask1(Ask1−/−) resulted in a marked functional defect in platelets. Ask1−/−platelets showed an impaired agonist-induced integrin αIIbβ3activation and platelet aggregation. Although there was no difference in Ca2+rise, platelet granule secretion and thromboxane A2(TxA2) generation were significantly attenuated in Ask1−/−platelets. The defective granule secretion observed in Ask1−/−platelets was a consequence of impaired TxA2generation. Biochemical studies showed that platelet agonists failed to activate p38 MAPK in Ask1−/−platelets. On the contrary, activation of c-Jun N-terminal kinases and extracellular signal-regulated kinase 1/2 MAPKs was augmented in Ask1−/−platelets. The defect in p38 MAPK results in failed phosphorylation of cPLA2in Ask1−/−platelets and impaired platelet aggregate formation under flow. The absence of Ask1 renders mice defective in hemostasis as assessed by prolonged tail-bleeding times. Deletion of Ask1also reduces thrombosis as assessed by delayed vessel occlusion of carotid artery after FeCl3-induced injury and protects against collagen/epinephrine-induced pulmonary thromboembolism. These results suggest that the platelet Ask1 plays an important role in regulation of hemostasis and thrombosis. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
