RhoG Protein Regulates Platelet Granule Secretion and Thrombus Formation in Mice
RhoG Protein Regulates Platelet Granule Secretion and Thrombus Formation in Mice
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DOI：
10.1074/jbc.m113.504100
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发表时间：
2013-11-22
影响因子：
4.8
通讯作者：
Poole, Alastair W.
中科院分区：
文献类型：
--
作者：
Goggs, Robert;Harper, Matthew T.;Poole, Alastair W.
背景：Rho家族GTP酶对正常血小板功能至关重要，但RhoG在血小板中的作用以前尚未研究。结果：RhoG基因敲除小鼠血小板颗粒分泌减少，血栓形成受损。结论：RhoG是血小板颗粒正常分泌所必需的。意义：RhoG是一种新型的血小板功能和血栓形成的调节剂，Rho GTP酶如Rac、RhoA和Cdc 42对正常血小板功能至关重要，但RhoG在血小板中的作用尚未研究。在其他细胞中，RhoG协调血小板功能不可或缺的过程，包括肌动蛋白细胞骨架重排和膜运输。因此，我们假设RhoG将在血小板中发挥关键作用。在这里，我们表明，RhoG在人类和小鼠血小板中表达，并通过胶原相关肽（CRP）和凝血酶刺激激活。我们使用RhoG（-/-）小鼠来研究RhoG在血小板中的功能。在CRP刺激的RhoG（-/-）血小板中，整合素活化和聚集减少，但对凝血酶的反应正常。RhoG（-/-）血小板的中心缺陷是CRP刺激后β颗粒、致密颗粒和溶酶体的分泌减少。整合素活化和聚集缺陷可以通过ADP共刺激来挽救，表明它们是致密颗粒分泌减少的结果。RhoG（-/-）血小板中致密颗粒分泌缺陷限制了额外血小板在体外流动血液中生长血栓的募集，并转化为体内血栓形成减少。有趣的是，RhoG（-/-）小鼠的尾部出血时间是正常的，这表明RhoG在血小板中的功能与血栓性疾病特别相关。
Background: Rho family GTPases are essential for normal platelet function, but the role of RhoG in platelets has not been studied previously. Results: Platelets lacking RhoG have reduced granule secretion, and RhoG null mice have impaired thrombus formation. Conclusion: RhoG is required for normal platelet granule secretion. Significance: RhoG is a novel regulator of platelet function and thrombosis.Rho GTPases such as Rac, RhoA, and Cdc42 are vital for normal platelet function, but the role of RhoG in platelets has not been studied. In other cells, RhoG orchestrates processes integral to platelet function, including actin cytoskeletal rearrangement and membrane trafficking. We therefore hypothesized that RhoG would play a critical role in platelets. Here, we show that RhoG is expressed in human and mouse platelets and is activated by both collagen-related peptide (CRP) and thrombin stimulation. We used RhoG(-/-) mice to study the function of RhoG in platelets. Integrin activation and aggregation were reduced in RhoG(-/-) platelets stimulated by CRP, but responses to thrombin were normal. The central defect in RhoG(-/-) platelets was reduced secretion from -granules, dense granules, and lysosomes following CRP stimulation. The integrin activation and aggregation defects could be rescued by ADP co-stimulation, indicating that they are a consequence of diminished dense granule secretion. Defective dense granule secretion in RhoG(-/-) platelets limited recruitment of additional platelets to growing thrombi in flowing blood in vitro and translated into reduced thrombus formation in vivo. Interestingly, tail bleeding times were normal in RhoG(-/-) mice, suggesting that the functions of RhoG in platelets are particularly relevant to thrombotic disorders.