Neuroprotection of Botch in experimental intracerebral hemorrhage in rats.
Neuroprotection of Botch in experimental intracerebral hemorrhage in rats.
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Botch对大鼠实验性脑出血的神经保护作用
DOI：
10.18632/oncotarget.20524
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发表时间：
2017-11-10
期刊：
影响因子：
--
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Mei B;Li H;Zhu J;Yang J;Yang Z;Wen Z;Li X;Shen H;Shen M;Chen G
NOTCH1的成熟参与了脑出血后的细胞凋亡和炎症反应。有报道称，Botch结合并阻止Notch1成熟。在这里，我们评估了Botch在脑出血继发性脑损伤中的作用和潜在的机制。用自体动脉血注入SD大鼠建立实验性脑出血模型，体外培养大鼠皮质神经元，用氧合血红蛋白模拟脑出血。构建了Glu115Ala突变的野生型Botch和野生型Botch的特异小干扰RNA和表达载体。血肿周围脑组织中Botch和Notch1跨膜胞内域(Notch1-TMIC)蛋白水平升高。Botch过表达导致未加工的Notch1全长形式增加，同时Notch1-TMIC显著下降，而Botch敲除导致Notch1-TMIC增加约1.5倍。脑出血后细胞凋亡、坏死和神经行为缺陷增加，这一变化可被Botch过表达所抑制，而被Botch基因敲除后被增强。双重免疫荧光显示，Botch和Notch1在反式高尔基体中共存。野生型Botch的过表达而不是Botch E115A突变体的过表达导致了Botch与Notch1之间的相互作用增加，减少了Notch1胞内结构域的形成和核定位，并减轻了细胞的凋亡和炎症。总之，Botch通过以Glu115依赖的方式拮抗Notch1的成熟，从而发挥神经保护作用。然而，内源性Botch介导的神经保护不足以逆转脑出血继发性脑损伤。
Notch1 maturation participates in apoptosis and inflammation following intracerebral hemorrhage (ICH). It has been reported that Botch bound to and blocked Notch1 maturation. Here we estimated the role of Botch in ICH-induced secondary brain injury and underlying mechanisms. Experimental ICH model was induced by autologous arterial blood injection in Sprague-Dawley rats, and cultured primary rat cortical neurons were exposed to oxyhemoglobin to mimic ICH in vitro. Specific small interfering RNAs and expression plasmids encoding wild type Botch and Botch with Glu115Ala mutation were exploited. The protein levels of Botch and Notch1 transmembrane intracellular domain (Notch1-TMIC) were increased within brain tissue around hematoma. Botch overexpression led to an increase in unprocessed Notch1 full-length form accompanied by a significant decrease in Notch1-TMIC, while Botch knockdown resulted in an approximately 1.5-fold increase in Notch1-TMIC. There were increased cell apoptosis, necrosis and neurobehavioral deficits after ICH, which was inhibited by Botch overexpression and enhanced by Botch knockdown. Double immunofluorescence showed a colocalization of Botch and Notch1 in the trans-Golgi. Overexpression of wild type Botch, but not Botch E115A mutant, led to an increase in the interaction between Botch and Notch1, reduced the formation and the nuclear localization of Notch1 intracellular domain, and attenuated cell apoptosis and inflammation. In conclusion, Botch exerts neuroprotection against neuronal damage via antagonizing the maturation of Notch1 in Glu115-denpendent manner. However, neuroprotection mediated by endogenous Botch is not enough to reverse ICH-induced secondary brain injury.
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