| First Author | Naik MU | Year | 2017 |
| Journal | Blood | Volume | 129 |
| Issue | 9 | Pages | 1197-1209 |
| PubMed ID | 28028021 | Mgi Jnum | J:240103 |
| Mgi Id | MGI:5882431 | Doi | 10.1182/blood-2016-07-729780 |
| Citation | Naik MU, et al. (2017) Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation. Blood 129(9):1197-1209 |
| abstractText | 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 alphaIIbbeta3 activation 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 TxA2 generation. 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 cPLA2 in 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 Ask1 also 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. |
