高血糖会加重缺血性脑卒中的预后，与血小板摄取葡萄糖无关。
Hyperglycemia exacerbates ischemic stroke outcome independent of platelet glucose uptake.
机构信息
University of Utah Molecular Medicine Program, Salt Lake City, UT, USA.
Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
出版信息
J Thromb Haemost. 2021 Feb;19(2):536-546. doi: 10.1111/jth.15154. Epub 2020 Nov 27.
OBJECTIVE
Hyperglycemia is a common comorbidity for ischemic stroke and is associated with worsened neurological outcomes. Platelets are central mediators of ischemic stroke and hyperglycemia mediates platelet hyperactivity. In this study, we investigated the contribution of platelet glucose metabolism to ischemic stroke.
METHODS
Mice lacking both Glut1 and Glut3 specifically in platelets (DKO) and their littermate controls (WT) were subjected to 1-hour transient middle cerebral artery occlusion under normoglycemic and streptozotocin-induced hyperglycemic conditions after which stroke outcomes, platelet activation, and platelet-neutrophil aggregate (PNA) formation were examined.
RESULTS
Under normoglycemic conditions, DKO mice were protected from ischemic stroke with smaller brain infarct volumes and improved cerebral blood flow. In addition, DKO mice had reduced platelet activation, PNA, and cerebral neutrophil recruitment after stroke. Hyperglycemia significantly increased infarct size and cerebral Evans blue extravasation and worsened neurological outcomes and cerebral blood flow in both WT and DKO mice, abolishing the protective effect witnessed under normoglycemic conditions. Flow cytometric analysis after stroke demonstrated increased platelet activation and neutrophil trafficking to the brain, independent of platelet glucose metabolism. Finally, platelets from healthy DKO mice were unable to become procoagulant upon dual agonist stimulation. Conversely, hyperglycemia increased platelet mitochondrial reactive oxygen species production which potentiated procoagulant platelet formation in WT mice and restored procoagulant platelet formation in DKO mice.
CONCLUSION
Hyperglycemia aggravates ischemic stroke outcome independent of platelet glucose uptake. Furthermore, we demonstrated that hyperglycemia primes procoagulant platelet formation. This underlines the therapeutic potential for strategies targeting procoagulant platelet formation for the treatment of acute ischemic stroke.
目的
高血糖是缺血性中风的常见合并症，并与神经功能恶化有关。血小板是缺血性中风的主要中介物，高血糖介导血小板活性增强。在这项研究中，我们研究了血小板葡萄糖代谢对缺血性中风的贡献。
方法
缺乏血小板中 Glut1 和 Glut3 的敲除小鼠（DKO）及其同窝对照（WT）在正常血糖和链脲佐菌素诱导的高血糖条件下接受 1 小时短暂性大脑中动脉闭塞，然后检查中风结果、血小板活化和血小板-中性粒细胞聚集体（PNA）形成。
结果
在正常血糖条件下，DKO 小鼠对缺血性中风具有保护作用，脑梗死体积较小，脑血流改善。此外，DKO 小鼠在中风后血小板活化、PNA 和脑中性粒细胞募集减少。高血糖显著增加梗死面积和脑 Evans 蓝外渗，并恶化 WT 和 DKO 小鼠的神经功能和脑血流，消除了在正常血糖条件下观察到的保护作用。中风后的流式细胞术分析表明，血小板活化和中性粒细胞向大脑的转移增加，与血小板葡萄糖代谢无关。最后，来自健康 DKO 小鼠的血小板在双重激动剂刺激下无法成为促凝剂。相反，高血糖增加了血小板线粒体活性氧的产生，增强了 WT 小鼠的促凝血小板形成，并恢复了 DKO 小鼠的促凝血小板形成。
结论
高血糖加重缺血性中风的后果，与血小板葡萄糖摄取无关。此外，我们证明了高血糖使促凝血小板形成成为可能。这强调了针对促凝血小板形成的治疗策略在治疗急性缺血性中风方面的潜在治疗价值。
Zotero 插件