Hyperglycemia exacerbates ischemic stroke outcome independent of platelet glucose uptake.
Hyperglycemia exacerbates ischemic stroke outcome independent of platelet glucose uptake.
复制标题
高血压加重缺血性卒中结局与血小板葡萄糖摄取无关。
DOI：
10.1111/jth.15154
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Campbell RA
中科院分区：
文献类型：
--
作者：
Denorme F;Portier I;Kosaka Y;Campbell RA
高血压是缺血性卒中的常见合并症，与神经系统结局恶化相关。血小板是缺血性卒中的中心介质，高血糖介导血小板过度活跃。在这项研究中，我们研究了血小板葡萄糖代谢在缺血性卒中中的作用。在正常血糖和链脲佐菌素诱导的高血糖条件下，对血小板特异性缺乏Glut 1和Glut 3的小鼠（DKO）及其同窝对照（WT）进行1小时短暂性大脑中动脉闭塞，然后检查每搏输出量、血小板活化和血小板-中性粒细胞聚集体（PNA）形成。在血糖正常的条件下，DKO小鼠受到保护，免于缺血性中风，脑梗死体积较小，脑血流量改善。此外，DKO小鼠中风后血小板活化、PNA和脑中性粒细胞募集减少。在WT和DKO小鼠中，高血压显著增加了梗死面积和脑伊文思蓝外渗，并使神经功能结局和脑血流量恶化，消除了在血糖正常条件下观察到的保护作用。中风后的流式细胞术分析显示血小板活化和中性粒细胞向脑的运输增加，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后不能成为促凝血剂。相反，高血糖增加血小板线粒体ROS的产生，这增强了WT小鼠中促凝血血小板的形成，并恢复了DKO小鼠中促凝血血小板的形成。血小板葡萄糖摄取不依赖于高血糖升高缺血性卒中的结局。此外，我们证明高血糖引发促凝血血小板形成。这强调了靶向促凝血血小板形成策略治疗急性缺血性卒中的治疗潜力。
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. Mice lacking both Glut1 and Glut3 specifically in platelets (DKO) and their littermate controls (WT) were subjected to one-hour transient middle cerebral artery occlusion under normoglycemic and streptozotocin-induced hyperglycemic conditions after which, stroke volume, platelet activation, and platelet-neutrophil aggregate (PNA) formation were examined. 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, PNAs, 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 ROS production which potentiated procoagulant platelet formation in WT mice and restored procoagulant platelet formation in DKO mice. 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.
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影响因子：
8.3
作者：
Bieber, Michael;Gronewold, Janine;Hermann, Dirk M.
通讯作者：
Hermann, Dirk M.
影响因子：
9.9
作者：
Williams, LS;Rotich, J;Tierney, WR
通讯作者：
Tierney, WR
影响因子：
8.3
作者：
Kraft, Peter;Schuhmann, Michael K.;Kleinschnitz, Christoph
通讯作者：
Kleinschnitz, Christoph
DOI：
10.1161/atvbaha.112.300433
发表时间：
2012-12
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Choo HJ;Saafir TB;Mkumba L;Wagner MB;Jobe SM
通讯作者：
Jobe SM
影响因子：
7.7
作者：
Kopprasch, S;Pietzsch, J;Graessler, J
通讯作者：
Graessler, J