Platelets, anucleated megakaryocyte (MK)-derived cells, play a major role in hemostasis and arterial thrombosis. Although protein kinase casein kinase 2 (CK2) is readily detected in MKs and platelets, the impact of CK2-dependent signaling on MK/platelet (patho-)physiology has remained elusive. The present study explored the impact of the CK2 regulatory β-subunit on platelet biogenesis and activation. MK/platelet-specific genetic deletion of CK2β (ck2β-/- ) in mice resulted in a significant macrothrombocytopenia and an increased extramedullar megakaryopoiesis with an enhanced proportion of premature platelets. Although platelet life span was only mildly affected, ck2β-/- MK displayed an abnormal microtubule structure with a drastically increased fragmentation within bone marrow and a significantly reduced proplatelet formation in vivo. In ck2β-/- platelets, tubulin polymerization was disrupted, resulting in an impaired thrombopoiesis and an abrogated inositol 1,4,5-triphosphate receptor-dependent intracellular calcium (Ca2+) release. Presumably due to a blunted increase in the concentration of cytosolic Ca2+, activation-dependent increases of α and dense-granule secretion and integrin αIIbβ3 activation, and aggregation were abrogated in ck2β-/- platelets. Accordingly, thrombus formation and stabilization under high arterial shear rates were significantly diminished, and thrombotic vascular occlusion in vivo was significantly blunted in ck2β-/- mice, accompanied by a slight prolongation of bleeding time. Following transient middle cerebral artery occlusion, ck2β-/- mice displayed significantly reduced cerebral infarct volumes, developed significantly less neurological deficits, and showed significantly better outcomes after ischemic stroke than ck2βfl/fl mice. The present observations reveal CK2β as a novel powerful regulator of thrombopoiesis, Ca2+-dependent platelet activation, and arterial thrombosis in vivo.

中文翻译：

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CK2β 在体内动脉血栓形成中严重调节血小板生成和 Ca 2+ 触发的血小板激活

血小板，无核巨核细胞 (MK) 衍生细胞，在止血和动脉血栓形成中起主要作用。尽管蛋白激酶酪蛋白激酶 2 (CK2) 在 MK 和血小板中很容易检测到，但依赖 CK2 的信号传导对 MK/血小板（病理）生理学的影响仍然难以捉摸。本研究探讨了 CK2 调节 β 亚基对血小板生物发生和活化的影响。小鼠中 CK2β (ck2β-/- ) 的 MK/血小板特异性基因缺失导致显着的巨血小板减少症和髓外巨核细胞生成增加，并增加早产血小板的比例。尽管血小板寿命仅受到轻微影响，但 ck2β-/- MK 显示出异常的微管结构，骨髓内碎裂急剧增加，体内血小板形成显着减少。在 ck2β-/- 血小板中，微管蛋白聚合被破坏，导致血小板生成受损和肌醇 1,4,5-三磷酸受体依赖性细胞内钙 (Ca2+) 释放被消除。推测是由于细胞溶质 Ca2+ 浓度的缓慢增加，α 和致密颗粒分泌的激活依赖性增加以及整合素 αIIbβ3 激活和聚集在 ck2β-/- 血小板中被取消。因此，高动脉剪切速率下的血栓形成和稳定显着减少，ck2β-/-小鼠体内血栓形成的血管闭塞明显减弱，同时出血时间略有延长。在短暂的大脑中动脉闭塞后，ck2β-/- 小鼠的脑梗塞体积显着减少，神经功能缺损显着减少，并且在缺血性中风后显示出比 ck2βfl/fl 小鼠更好的结果。目前的观察结果表明，CK2β 是体内血小板生成、Ca2+ 依赖性血小板活化和动脉血栓形成的新型强大调节剂。