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Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation
| Content Provider | Scilit |
|---|---|
| Author | Naik, Meghna U. Patel, Pravin Derstine, Randall Turaga, Ramya Chen, Xi Golla, Kalyan Neeves, Keith B. Ichijo, Hidenori Naik, Ulhas P. |
| Copyright Year | 2017 |
| Abstract | 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 αIIbβ3 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. Publisher9s Note: There is an Inside Blood Commentary on this article in this issue. Key Points ASK1 regulates TxA2 generation through p38 MAPK-dependent phosphorylation of cPLA2. Because of impaired platelet function, Ask1−/− mice are protected from arterial thrombosis and pulmonary thromboembolism. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374734/pdf |
| Ending Page | 1209 |
| Page Count | 13 |
| Starting Page | 1197 |
| DOI | 10.1182/blood-2016-07-729780 |
| Journal | Blood |
| Issue Number | 9 |
| Volume Number | 129 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2017-03-02 |
| Access Restriction | Open |
| Subject Keyword | Research and Experimental Medicine Functional Platelet Hemostasis and Thrombosis Apoptosis Mapks Ask1 Regulates Signal Regulated Journal: Blood (Vol- 111, Issue- 9) |
| Content Type | Text |
| Resource Type | Article |
