Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Faculty of Health Sciences, University of Hull, HU6 7RX Hull, UK.
Department of Internal Medicine 1, University Hospital, RWTH Aachen, 52074 Aachen, Germany.
Cells. 2019 Feb 11;8(2):149. doi: 10.3390/cells8020149.
Typical Rho GTPases, such as Rac1, Cdc42, and RhoA, act as molecular switches regulating various aspects of platelet cytoskeleton reorganization. The loss of these enzymes results in reduced platelet functionality. Atypical Rho GTPases of the RhoBTB subfamily are characterized by divergent domain architecture. One family member, RhoBTB3, is expressed in platelets, but its function is unclear. In the present study we examined the role of RhoBTB3 in platelet function using a knockout mouse model. We found the platelet count, size, numbers of both alpha and dense granules, and surface receptor profile in these mice were comparable to wild-type mice. Deletion of had no effect on aggregation and dense granule secretion in response to a range of agonists including thrombin, collagen, and adenosine diphosphate (ADP). By contrast, alpha-granule secretion increased in mice lacking RhoBTB3 in response to thrombin, collagen related peptide (CRP) and U46619/ADP. Integrin activation and spreading on fibrinogen and collagen under static conditions were also unimpaired; however, we observed reduced platelet accrual on collagen under flow conditions. These defects did not translate into alterations in tail bleeding time. We conclude that genetic deletion of leads to subtle alterations in alpha-granule secretion and adhesion to collagen without significant effects on hemostasis in vivo.
典型的 Rho GTPases，如 Rac1、Cdc42 和 RhoA，作为分子开关调节血小板细胞骨架重组的各个方面。这些酶的缺失会导致血小板功能降低。RhoBTB 亚家族的非典型 Rho GTPases 具有不同的结构域架构。该家族的一个成员 RhoBTB3 在血小板中表达，但功能尚不清楚。在本研究中，我们使用敲除小鼠模型研究了 RhoBTB3 在血小板功能中的作用。我们发现这些小鼠的血小板计数、大小、α 和致密颗粒的数量以及表面受体谱与野生型小鼠相当。缺失 对一系列激动剂（包括凝血酶、胶原蛋白和二磷酸腺苷 (ADP)）引起的聚集和致密颗粒分泌没有影响。相比之下，缺乏 RhoBTB3 的小鼠对凝血酶、胶原蛋白相关肽 (CRP) 和 U46619/ADP 的反应中α-颗粒分泌增加。在静态条件下整合素的激活和在纤维蛋白原和胶原蛋白上的扩展也不受影响；然而，我们观察到在流动条件下胶原蛋白上血小板的积累减少。这些缺陷并没有转化为尾部出血时间的改变。我们得出结论， 基因缺失导致α-颗粒分泌和与胶原蛋白粘附的细微改变，而对体内止血没有明显影响。
