The role of aquaporin 4 in apoptosis after intracerebral hemorrhage.
The role of aquaporin 4 in apoptosis after intracerebral hemorrhage.
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水通道蛋白4在脑出血后细胞凋亡中的作用
DOI：
10.1186/s12974-014-0184-5
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发表时间：
2014-10-31
影响因子：
9.3
通讯作者：
Dong Q
中科院分区：
文献类型：
--
作者：
Chu H;Xiang J;Wu P;Su J;Ding H;Tang Y;Dong Q
背景我们先前报道了小鼠脑出血后水通道蛋白-4缺失(AQP4-/-)增加了水肿，改变了血脑屏障的完整性。到目前为止，对AQP4在脑出血后细胞凋亡中的作用知之甚少。本研究旨在利用AQP4-/-小鼠研究AQP4在脑出血后细胞凋亡中的作用及其机制。方法比较野生型(AQP4+/+)小鼠和AQP4-/-小鼠脑出血后的存活率和神经功能缺失情况。用末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记(TUNEL)染色和Hoechst染色检测组织学改变。通过免疫细胞化学研究确定所涉及的细胞类型。分别于脑出血后1、3、7d用免疫印迹法检测caspase-3、caspase-9、caspase-8、Bax、Bcl2的活性。用细胞因子蛋白分析法检测脑出血后AQP4+/+和AQP4-/-小鼠的细胞因子，并用ELISA进行验证。结果脑出血后AQP4-/-小鼠出现较多的细胞凋亡，细胞类型以神经元和星形胶质细胞为主。Western blotting显示活化的caspase-3和caspase-8的表达显著增加(P<；0.05)。此外，细胞因子蛋白分析和Western blotting显示，脑出血后AQP4-/-小鼠的肿瘤坏死因子-Α和IL-1Β及其受体的释放比AQP4+/+小鼠有更大的促进作用(P<；0.05)。与野生型小鼠相比，AQP4-Α和IL-1Β抑制剂可减少脑出血后细胞的凋亡(P<；0.05)。结论AQP4基因缺失可促进脑出血后细胞的凋亡，其机制可能是通过细胞因子，尤其是肿瘤坏死因子-Α和IL-1Β，启动细胞凋亡级联反应，以及激活caspase-3和caspase-8。
BackgroundWe previously reported that aquaporin-4 deletion (AQP4-/-) in mice increased edema and altered blood-brain barrier integrity following intracerebral hemorrhage (ICH). To date, little is known about the role of AQP4 in apoptosis after ICH. The purpose of this study was to examine the role of AQP4 in apoptosis and its mechanisms after ICH using AQP4-/-mice.MethodsWe compared the survival rate and neurological deficits in wild-type (AQP4+/+) mice with those in AQP4-/-mice following ICH. Histological changes were detected with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining and Hoechst staining. The cell types involved were determined by immunocytochemical studies. We also measured activated caspase-3, caspase-9, caspase-8, Bax, and Bcl-2 with Western blotting at 1, 3, and 7 days after ICH. A cytokine protein assay was used to detect cytokines in AQP4+/+and AQP4-/-mice following ICH, and the results were verified by ELISA.ResultsWe found more apoptotic cells in AQP4-/-mice following ICH; the cell types involved were predominantly neurons and astrocytes. Western blotting showed that the expression of activated caspase-3 and caspase-8 was significantly increased (P<0.05). Moreover, we demonstrated a greater enhancement in the release of TNF-Α and IL-1Β, as well as their receptors, in AQP4-/-mice following ICH than in AQP4+/+mice by cytokine protein assay and Western blotting (P<0.05). The inhibitors of TNF-Α and IL-1Β reduced apoptotic cells after ICH in AQP4-/-mice compared with wild-type mice (P<0.05).ConclusionsAQP4 deletion increases apoptosis following ICH, and the underlying mechanism may be through cytokines, especially TNF-Α and IL-1Β, initiating the apoptotic cascade, as well as activation of caspase-3 and caspase-8.
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