Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation
Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation
复制标题
DOI：
10.1161/atvbaha.117.309184
复制
发表时间：
2017-09-01
影响因子：
8.7
通讯作者：
Abel, E. Dale
中科院分区：
文献类型：
--
作者：
Fidler, Trevor P.;Middleton, Elizabeth A.;Abel, E. Dale
目的：在活化过程中，血小板增加葡萄糖摄取、糖酵解和葡萄糖氧化并消耗储存的糖原。葡萄糖代谢与血小板功能之间的相关性尚不清楚，而体内葡萄糖代谢对血小板功能的作用则知之甚少。葡萄糖要进入细胞，必须通过葡萄糖转运蛋白进行转运。在这里，我们评估GLUT3（葡萄糖转运蛋白3）对血小板功能的贡献，以更好地了解血小板中的葡萄糖代谢。方法和结果：将GLUT3连接等位基因的小鼠与PF4（血小板因子4）驱动的Cre重组酶杂交，产生了GLUT3的血小板特异性敲除。在血小板中，GLUT3主要定位于a-颗粒膜上，在基础条件下促进葡萄糖摄取到a-颗粒中用于糖酵解。激活后，血小板脱粒，GLUT3转运到质膜，这是激活介导的葡萄糖摄取增加的原因。在体内，在肺栓塞的胶原/肾上腺素模型中，血小板中GLUT3的缺失增加了生存率，在自身免疫性炎症疾病的K/BxN模型中，血小板特异性GLUT3敲除小鼠显示出疾病进展减慢。从机制上讲，GLUT3的缺失降低了血小板脱粒、扩散和凝块缩回。a颗粒脱粒减少部分是由于GLUT3增强胞吐作用的能力受损。结论- glut3介导的葡萄糖利用和血小板糖原溶解促进a颗粒释放、血小板活化和活化后功能。
Objective-On activation, platelets increase glucose uptake, glycolysis, and glucose oxidation and consume stored glycogen. This correlation between glucose metabolism and platelet function is not well understood and even less is known about the role of glucose metabolism on platelet function in vivo. For glucose to enter a cell, it must be transported through glucose transporters. Here we evaluate the contribution of GLUT3 (glucose transporter 3) to platelet function to better understand glucose metabolism in platelets.Approach and Results-Platelet-specific knockout of GLUT3 was generated by crossing mice harboring GLUT3 floxed allele to a PF4 (platelet factor 4)-driven Cre recombinase. In platelets, GLUT3 is localized primarily on a-granule membranes and under basal conditions facilitates glucose uptake into a-granules to be used for glycolysis. After activation, platelets degranulate and GLUT3 translocates to the plasma membrane, which is responsible for activation-mediated increased glucose uptake. In vivo, loss of GLUT3 in platelets increased survival in a collagen/epinephrine model of pulmonary embolism, and in a K/BxN model of autoimmune inflammatory disease, platelet-specific GLUT3 knockout mice display decreased disease progression. Mechanistically, loss of GLUT3 decreased platelet degranulation, spreading, and clot retraction. Decreased a-granule degranulation is due in part to an impaired ability of GLUT3 to potentiate exocytosis.Conclusions-GLUT3-mediated glucose utilization and glycogenolysis in platelets promotes a-granule release, platelet activation, and postactivation functions.