Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia.
Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Platelets. 2023 Dec;34(1):2206921. doi: 10.1080/09537104.2023.2206921.
Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time ( < .005) and attenuated clot firmness ( < .005). ATV pre-treatment inhibited platelet aggregation and clot retraction. Binding of fibrinogen and P-selectin exposure on stimulated platelets was significantly lower following pre-treatment with ATV ( < .05). Confocal microscopy revealed that ATV significantly altered the structure of platelet-rich plasma clots, consistent with the reduced fibrinogen binding. ATV enhanced lysis of Chandler model thrombi 1.4-fold versus control ( < .05). Western blotting revealed that ATV induced a dose-dependent accumulation of unprenylated Rab27b and Rap1a in the platelet membrane. ATV dose-dependently inhibited ADP release from activated platelets. Exogenous GGPP rescued the prenylation of Rab27b and Rap1a, and partially restored the ADP release defect, suggesting these changes arise from reduced prenylation of Rab27b. These data demonstrate that statins attenuate platelet aggregation, degranulation, and binding of fibrinogen thereby having a significant impact on clot contraction and structure.
他汀类药物通过耗尽脂质法呢基焦磷酸（GGPP）来抑制异戊烯焦磷酸途径，从而损害蛋白质的prenylation。Rab27b 和 Rap1a 是参与致密颗粒分泌、血小板活化和调节的小 GTPase 蛋白。我们分析了他汀类药物对血小板中 Rab27b 和 Rap1a 的 prenylation 的影响，以及对纤维蛋白凝块特性的下游影响。全血血栓弹性描记法显示，阿托伐他汀（ATV）延迟了血栓形成时间（ < .005）并减弱了血栓硬度（ < .005）。ATV 预处理抑制了血小板聚集和血栓收缩。与 ATV 预处理相比，纤维蛋白原和 P-选择素暴露在受刺激的血小板上的结合显著降低（ < .05）。共聚焦显微镜显示，ATV 显著改变了富含血小板的血浆凝块的结构，这与纤维蛋白原结合减少一致。与对照组相比，ATV 使 Chandler 模型血栓的溶解增加了 1.4 倍（ < .05）。Western blot 显示，ATV 诱导血小板膜中未prenylated Rab27b 和 Rap1a 的剂量依赖性积累。ATV 剂量依赖性地抑制了从激活的血小板中释放 ADP。外源性 GGPP 挽救了 Rab27b 和 Rap1a 的 prenylation，并部分恢复了 ADP 释放缺陷，这表明这些变化是由于 Rab27b 的 prenylation 减少所致。这些数据表明，他汀类药物减弱了血小板聚集、脱颗粒和纤维蛋白原的结合，从而对血栓收缩和结构产生了重大影响。
