Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway
Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway
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DOI：
10.1038/sj.jcbfm.9600062
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发表时间：
2005-06-01
影响因子：
6.3
通讯作者：
Chen, J
中科院分区：
文献类型：
--
作者：
Gao, YQ;Signore, AP;Chen, J
c-Jun N-末端激酶（JNK）是一种重要的应激反应性激酶，可被各种形式的脑损伤激活。在这项研究中，我们已经研究了JNK激活的作用，在神经元细胞死亡的小鼠模型局灶性缺血和再灌注，此外，我们研究了JNK的机制，在细胞凋亡信号转导，集中在神经元信号通路。我们在这里表明，JNK活性诱导脑缺血后0.5至24小时。全身给予小分子JNK特异性抑制剂SP 600125可降低缺血后JNK活性，并呈剂量依赖性减少梗死体积。c-Jun N-末端激酶抑制也减弱缺血诱导的Bim、Hrk/DP 5和Fas的表达，但不减弱Bcl-2或FasL的表达。JNK抑制可阻止缺血诱导的Bax和Bim的线粒体易位、细胞色素c和Smac的释放以及caspase-9和caspase-3的激活，这有力地支持了JNK在促进线粒体凋亡信号通路中的作用。使用免疫共沉淀进一步研究了JNK促进缺血后Bax易位的潜在机制，结果显示JNK活化引起Bax的胞质螯合蛋白14-3-3的丝氨酸磷酸化，导致Bax从14-3-3解离并随后易位到线粒体。这些结果证实了JNK在缺血性脑损伤中作为一种重要的细胞死亡介质的作用，并表明JNK触发线粒体凋亡信号通路的机制之一是通过促进Bax和Bim易位。
c-Jun N-terminal kinase (JNK) is an important stress-responsive kinase that is activated by various forms of brain insults. In this study, we have examined the role of JNK activation in neuronal cell death in a murine model of focal ischemia and reperfusion; furthermore, we investigated the mechanism of JNK in apoptosis signaling, focusing on the mitochondrial-signaling pathway. We show here that JNK activity was induced in the brain 0.5 to 24h after ischemia. Systemic administration of SP600125, a small molecule JNK-specific inhibitor, diminished JNK activity after ischemia and dose-dependently reduced infarct volume. c-Jun N-terminal kinase inhibition also attenuated ischemia-induced expression of Bim, Hrk/DP5, and Fas, but not the expression of Bcl-2 or FasL. In strong support of a role for JNK in promoting the mitochondrial apoptosis-signaling pathway, JNK inhibition prevented ischemia-induced mitochondrial translocation of Bax and Bim, release of cytochrome c and Smac, and activation of caspase-9 and caspase-3. The potential mechanism by which JNK promoted Bax translocation after ischemia was further studied using coimmunoprecipitation, and the results revealed that JNK activation caused serine phosphorylation of 14-3-3, a cytoplasmic sequestration protein of Bax, leading to Bax disassociation from 14-3-3 and subsequent translocation to mitochondria. These results confirm the role of JNK as a critical cell death mediator in ischemic brain injury, and suggest that one of the mechanisms by which JNK triggers the mitochondrial apoptosis-signaling pathway is via promoting Bax and Bim translocation.