PFKFB3-mediated glycolysis is involved in reactive astrocyte proliferation after oxygen-glucose deprivation/reperfusion and is regulated by Cdh1
PFKFB3-mediated glycolysis is involved in reactive astrocyte proliferation after oxygen-glucose deprivation/reperfusion and is regulated by Cdh1
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DOI：
10.1016/j.neuint.2015.10.006
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发表时间：
2015-12-01
影响因子：
4.2
通讯作者：
Zhang, Chuanhan
中科院分区：
文献类型：
--
作者：
Lv, Youyou;Zhang, Bo;Zhang, Chuanhan
反应性星形胶质细胞增殖参与许多中枢退行性疾病。6磷酸果糖-2-激酶/果糖-2，6-二磷酸酶亚型3（PFKFB 3）是6磷酸果糖-1-激酶（PFK 1）的变构激活剂，控制糖酵解通量。此外，APC/C-Cdh 1通过调节PFKFB 3的表达在脑代谢中起着至关重要的作用。先前的研究已经确定了PFKFB 3介导的糖酵解在病理性血管生成、细胞自噬和增殖细胞中淀粉样蛋白斑块沉积中的作用。然而，PFKFB 3在脑缺血后反应性星形胶质细胞增殖中的作用尚不清楚。本研究采用原代培养大鼠皮层星形胶质细胞的方法，建立了模拟脑缺血的氧-糖剥夺/再灌注（OGD/R）模型。星形胶质细胞增殖通过增殖细胞核抗原（PCNA）的蛋白质印迹法和EdU掺入法测定。我们发现，OGD/R上调PFKFB 3和PFK 1的表达，这是伴随着反应性星形胶质细胞增殖。通过siRNA转染敲低PFKFB 3显著抑制反应性星形胶质细胞增殖和乳酸释放，乳酸释放是糖酵解的指标。我们发现，PFKFB 3和PFK 1的表达下调和乳酸释放减少时，OGD/R诱导的星形胶质细胞增殖抑制Cdh 1表达慢病毒。因此，通过控制APC/C-Cdh 1下游的糖酵解通量，通过下调PFKFB 3可以有效抑制反应性星形胶质细胞增殖。(C)2015爱思唯尔有限公司版权所有。
Reactive astrocyte proliferation is involved in many central degenerative diseases. The enzyme 6phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), an allosteric activator of 6phosphofructo-1-kinase (PFK1), controls glycolytic flux. Furthermore, APC/C-Cdh1 plays a crucial role in brain metabolism by regulating PFKFB3 expression. Previous studies have defined the roles of PFKFB3-mediated glycolysis in pathological angiogenesis, cell autophagy, and amyloid plaque deposition in proliferating cells. However, the role of PFKFB3 in reactive astrocyte proliferation after cerebral ischemia is unknown. In this study, we cultured rat primary cortical astrocytes and established an oxygen-glucose deprivation/reperfusion (OGD/R) model to mimic cerebral ischemia in vivo. Astrocyte proliferation was measured by western blotting for proliferating cell nuclear antigen (PCNA) and by EdU incorporation. We found that OGD/R up-regulated PFKFB3 and PFK1 expression, which was accompanied by reactive astrocyte proliferation. Knockdown of PFKFB3 by siRNA transfection significantly inhibited reactive astrocyte proliferation and lactate release, an indicator of glycolysis. We found that PFKFB3 and PFK1 expression were down-regulated and lactate release was decreased when OGD/R-induced astrocyte proliferation was inhibited by a Cdh1-expressing lentivirus. Thus, reactive astrocyte proliferation can be effectively suppressed by down-regulation of PFKFB3 through control of glycolytic flux, which is downstream of APC/C-Cdh1. (C) 2015 Elsevier Ltd. All rights reserved.