CD44 sensitivity of platelet activation, membrane scrambling and adhesion under high arterial shear rates
CD44 sensitivity of platelet activation, membrane scrambling and adhesion under high arterial shear rates
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DOI：
10.1160/th14-10-0847
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发表时间：
2016-01-01
影响因子：
6.7
通讯作者：
Lang, Florian
中科院分区：
文献类型：
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作者：
Liu, Guilai;Liu, Guoxing;Lang, Florian
CD 44是巨噬细胞迁移抑制因子（MIF）（一种抗凋亡促炎细胞因子）信号传导所必需的。MIF由血小板表达和释放，血小板是闭塞性血管疾病的关键参与者。关于CD 44在血小板功能调节中的作用尚不清楚。因此，本研究探讨了CD 44是否改变了脱粒（P-选择素暴露）、整合素活化、半胱天冬酶活性、血小板表面的磷脂酰丝氨酸暴露、血小板体积、Orai 1蛋白丰度和胞质Ca 2+活性（[Ca 2 +]（i））。将来自缺乏CD 44的小鼠（cd 44（-/-））的血小板与来自相应野生型小鼠（cd 44（+/+））的血小板进行比较。在静息血小板中，两种基因型的P-选择素丰度、α（IIb）β（3）整合素活化、半胱天冬酶-3活性和磷脂酰丝氨酸暴露可忽略不计，而cd 44（-/-）和cd 44（+/+）血小板中Orai 1蛋白丰度、[Ca 2 +]（i）和体积相似。凝血酶（0.02 U/ml）、胶原相关肽（CRP，2 μ g/ml）和用毒胡萝卜素（1 μ M）耗竭钙库可显著增加血小板脱颗粒和α（IIb）β（3）整合素活化，对cd 44（-/-）血小板的作用比cd 44（+/+）血小板更明显。凝血酶（0.02 U/ml）增加血小板[Ca 2 +] i、caspase-3活性、磷脂酰丝氨酸暴露和Orai 1表面丰度，在cd 44（-/-）中的作用再次显著强于cd 44（+/+）血小板。凝血酶进一步降低cd 44（-/-）和cd 44（+/+）血小板的前向散射，这种作用在cd 44（-/-）血小板中比在cd 44（+/+）血小板中更明显。在cd 44（-/-）小鼠中，在高动脉剪切率（1,700 s（-1））下血小板粘附和体外血栓形成显著增加。总之，CD 44的遗传缺陷增强了血小板的活化、凋亡和促血栓形成能力。
CD44 is required for signalling of macrophage migration inhibitory factor (MIF), an anti-apoptotic pro-inflammatory cytokine. MIF is expressed and released from blood platelets, key players in the orchestration of occlusive vascular disease. Nothing is known about a role of CD44 in the regulation of platelet function. The present study thus explored whether CD44 modifies degranulation (P-selectin exposure), integrin activation, caspase activity, phosphatidylserine exposure on the platelet surface, platelet volume, Orai1 protein abundance and cytosolic Ca2+-activity ([Ca2+](i)). Platelets from mice lacking CD44 (cd44(-/-)) were compared to platelets from corresponding wild-type mice (cd44(+/+)). In resting platelets, P-selectin abundance, alpha(IIb)beta(3) integrin activation, caspase-3 activity and phosphatidylserine exposure were negligible in both genotypes and Orai1 protein abundance, [Ca2+](i), and volume were similar in cd44(-/-) and cd44(+/+) platelets. Platelet degranulation and alpha(IIb)beta(3) integrin activation were significantly increased by thrombin (0.02 U/ml), collagen related peptide (CRP, 2 mu g/ml and Ca2+-store depletion with thapsigargin (1 mu M), effects more pronounced in cd44(-/-) than in cd44(+/+) platelets. Thrombin (0.02 U/ml) increased platelet [Ca2+] i, caspase-3 activity, phosphatidylserine exposure and Orai1 surface abundance, effects again significantly stronger in cd44(-/-) than in cd44(+/+) platelets. Thrombin further decreased forward scatter in cd44(-/-) and cd44(+/+) platelets, an effect which tended to be again more pronounced in cd44(-/-) than in cd44(+/+) platelets. Platelet adhesion and in vitro thrombus formation under high arterial shear rates (1,700 s(-1)) were significantly augmented in cd44(-/-) mice. In conclusion, genetic deficiency of CD44 augments activation, apoptosis and prothrombotic potential of platelets.