The impact of neuronal Notch-1/JNK pathway on intracerebral hemorrhage-induced neuronal injury of rat model.
The impact of neuronal Notch-1/JNK pathway on intracerebral hemorrhage-induced neuronal injury of rat model.
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DOI：
10.18632/oncotarget.12094
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发表时间：
2016-11-08
期刊：
影响因子：
--
通讯作者：
Dai J
中科院分区：
文献类型：
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作者：
Chen M;Sun J;Lu C;Chen X;Ba H;Lin Q;Cai J;Dai J
Notch信号是一种高度保守的信号通路，在胚胎发育过程中调节细胞命运决定。Notch激活通过调节NF-κB和HIF-1α通路危害神经元，然而，Notch信号通路在脑出血（ICH）后激活JNK/c-Jun中的作用尚未研究。在这项研究中，我们使用大鼠ICH模型和凝血酶诱导的细胞模型来研究Notch-1/JNK信号的潜在作用。我们的研究结果显示，在缺血条件下，脑出血后血肿周围神经元组织中Notch-1和JNK增加（均p<0.05）。此外，脑出血后caspase-3活性蛋白的表达也明显上调。根据体外测定，Notch-1、p-JNK和活性caspase-3的表达在细胞活力降低的ICH细胞模型中均上调（均p<0.05）。而阻断Notch-1或JNK均能抑制JNK的磷酸化和活性caspase-3的表达，细胞活力明显改善。结论：Notch-1通过激活JNK通路，诱导caspase-3的活化，在脑出血或缺血时引起神经元损伤。因此，Notch-1/JNK信号通路在脑出血过程中具有重要作用，可能成为防治脑损伤的治疗靶点。
Notch signaling is a highly conserved pathway that regulates cell fate decisions during embryonic development. Notch activation endangers neurons by modulating NF-κB and HIF-1α pathways, however, the role of Notch signaling in activating JNK/c-Jun following intracerebral hemorrhage (ICH) has not been investigated. In this study, we used rat ICH models and thrombin-induced cell models to investigate the potential role of Notch-1/JNK signals. Our findings revealed that Notch-1 and JNK increased in hematoma-surrounding neurons tissues following ICH during ischemic conditions (all p<0.05). Besides, the expression of active caspase-3 protein was also up-regulated after ICH. According to in-vitro assays, the expression of Notch-1, p-JNK, and active caspase-3 were all up-regulated in cell viability-decreasing ICH cell models (all p<0.05). However, blocking of either Notch-1 or JNK suppressed the phosphorylation of JNK and the expression of active caspase-3, and cell viability was obviously ameliorated. In conclusion, this work suggested Notch-1 activates JNK pathway to induce the active caspase-3, leading to neuronal injury when intracerebral hemorrhage or ischemia occurred. Thus the Notch-1/JNK signal pathway has an important role in ICH process, and may be a therapeutic target to prevent brain injury.