Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo
Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo
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DOI：
10.2353/ajpath.2006.050765
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发表时间：
2006-01-01
影响因子：
6
通讯作者：
Harada, T
中科院分区：
文献类型：
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作者：
Harada, C;Nakamura, K;Harada, T
凋亡信号调节激酶1 （Apoptosis signal- regulatory kinase 1, ASK1）是一种丝裂原激活的蛋白激酶激酶，在氧化应激诱导的细胞凋亡中起重要作用。在本研究中，我们使用ASK1敲除（KO）小鼠来研究ASK1参与视网膜发育和缺血性损伤期间发生的神经细胞凋亡的可能性。ASK1在视网膜神经元中表达，包括视网膜神经节细胞（RGCs），但ASK1 KO小鼠在发育过程中视网膜结构和细胞死亡程度正常。另一方面，该品系对缺血性损伤的敏感性较低，存活的视网膜神经元数量较野生型小鼠显著增加。有趣的是，缺血诱导的p38丝裂原活化蛋白激酶（p38）磷酸化介导RGC凋亡，在ASK1 KO小鼠中几乎完全被抑制。在这些视网膜中，与野生型小鼠相比，裂解的caspase-3-和TUNEL阳性神经元的数量明显减少。此外，培养的ASK1 KO小鼠RGCs对h2o2诱导的细胞凋亡具有抗性。我们的研究结果表明，ASK1参与了各种氧化应激后神经细胞的凋亡。因此，抑制ASK1-p38通路可能有助于治疗包括青光眼在内的神经退行性疾病。
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in oxidative stress-induced apoptosis. In the present study, we used ASK1 knockout (KO) mice to examine the possibility that ASK1 is involved in the neural cell apoptosis that occurs during retinal development and ischemic injury. ASK1 was expressed in retinal neurons, including retinal ganglion cells (RGCs), but retinal structure and extent of cell death during development were normal in ASK1 KO mice. On the other hand, the strain was less susceptible to ischemic injury, and the number of surviving retinal neurons was significantly increased compared with that in wild type mice. Interestingly, ischemia induced phosphorylation of p38 mitogen-activated protein kinase (p38), which mediates RGC apoptosis, was almost completely suppressed in ASK1 KO mice. In such retinas, the numbers of cleaved caspase-3- and TUNEL,positive neurons were apparently decreased compared with those in wild-type mice. Furthermore, cultured RGCs from ASK1 KO mice were resistant to H2O2-induced apoptosis. Our findings suggest that ASK1 is involved in the neural cell apoptosis after various kinds of oxidative stress. Thus, inhibition of the ASK1-p38 pathway could he useful for the treatment of neurodegenerative diseases including glaucoma.