GDF-15 prevents platelet integrin activation and thrombus formation
GDF-15 prevents platelet integrin activation and thrombus formation
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DOI：
10.1111/jth.12100
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发表时间：
2013-02-01
影响因子：
10.4
通讯作者：
Zarbock, A.
中科院分区：
文献类型：
--
作者：
Rossaint, J.;Vestweber, D.;Zarbock, A.
背景整合素介导的血小板功能在原发性止血中起重要作用。生长分化因子15（GDF-15）已被证明能抑制白细胞中β 2-整联蛋白的活化。方法在体外和不同的体内血栓形成模型中研究GDF-15对血小板整合素活化的影响。结果GDF-15-/-小鼠在胶原诱导的肺血栓栓塞后，血栓形成加速，存活率降低。在重建实验中，重组GDF-15减慢血栓形成并延长出血时间。体外实验表明，GDF-15预处理，激动剂刺激的血小板显示降低结合纤维蛋白原在流动室测定和减少激活的1-和3-整联蛋白在流式细胞术实验。用GDF-15预处理人和小鼠血小板减少血小板聚集。在机制上，GDF-15通过激活PKA阻止激动剂诱导的Rap 1依赖性IIb 3激活。刺激后血小板P-选择素表达和致密颗粒分泌不受GDF-15的影响，表明GDF-15对整合素活化的特异性作用。结论GDF-15特异性抑制血小板整合素活化。这些发现可能对涉及血小板的止血条件的治疗具有深远的临床意义。
Background Integrin-mediated platelet function plays an important role in primary hemostasis. Growth-differentiation factor 15 (GDF-15) has been shown to inhibit 2-integrin activation in leukocytes. Methods We investigated the effect of GDF-15 on platelet integrin activation in vitro and in different in vivo models of thrombus formation. Results GDF-15-/- mice showed an accelerated thrombus formation and a reduced survival rate after collagen-induced pulmonary thromboembolism. In reconstitution experiments, recombinant GDF-15 decelerated thrombus formation and prolonged the bleeding time. In vitro experiments demonstrated that GDF-15 pretreated, agonist-stimulated platelets showed decreased binding to fibrinogen in flow chamber assays and reduced activation of 1- and 3-integrins in flow cytometry experiments. Pretreating human and mouse platelets with GDF-15 reduced platelet aggregation. Mechanistically, GDF-15 prevents agonist-induced Rap1- dependent IIb3 activation by activating PKA. Platelet P-selectin expression and dense granule secretion after stimulation were unaffected by GDF-15, indicating a specific effect of GDF-15 on integrin activation. Conclusion GDF-15 specifically inhibits platelet integrin activation. These findings may have profound clinical implications for the treatment of hemostatic conditions involving platelets.