Nuclear translocation and calpain-dependent reduction of Bcl-2 after neonatal cerebral hypoxia–ischemia
Nuclear translocation and calpain-dependent reduction of Bcl-2 after neonatal cerebral hypoxia–ischemia
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DOI：
10.1016/j.bbi.2009.09.013
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发表时间：
2010-07
期刊：
影响因子：
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通讯作者：
Changlian Zhu;U. Hallin;Y. Ozaki;Rita Grandér;K. Gatzinsky;B. Bahr;J. Karlsson;F. Shibasaki;H. Ha
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文献类型：
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作者：
Changlian Zhu;U. Hallin;Y. Ozaki;Rita Grandér;K. Gatzinsky;B. Bahr;J. Karlsson;F. Shibasaki;H. Ha
凋亡相关机制在新生儿脑缺氧缺血损伤的病理生理学中具有重要意义。半胱天冬酶是细胞凋亡的主要执行者，但有许多上游参与者影响细胞死亡途径。Bcl-2家族蛋白是线粒体通透性的重要调节剂，起促进或防止细胞凋亡的作用。本研究旨在探讨新生8日龄大鼠脑缺氧缺血（HI）后Bcl-2蛋白的抗凋亡作用。Bcl-2易位到细胞核，并积累在HI后再灌注的第一个24小时，通过免疫组织化学和免疫电镜判断。我们还发现，总的Bcl-2水平下降后HI在体内和离子载体的挑战后，在体外培养的人神经母细胞瘤（IMR-32）细胞。此外，Bcl-2的减少是钙蛋白酶依赖性的，因为它可以通过钙蛋白酶抑制剂CX 295在体内和体外阻止，这表明兴奋性毒性和凋亡机制之间的串扰。
Apoptosis-related mechanisms are important in the pathophysiology of hypoxic–ischemic injury in the neonatal brain. Caspases are the major executioners of apoptosis, but there are a number of upstream players that influence the cell death pathways. The Bcl-2 family proteins are important modulators of mitochondrial permeability, working either to promote or prevent apoptosis. In this study we focused on the anti-apoptotic Bcl-2 protein after neonatal cerebral hypoxia–ischemia (HI) in 8-day-old rats. Bcl-2 translocated to nuclei and accumulated there over the first 24h of reperfusion after HI, as judged by immunohistochemistry and immuno-electron microscopy. We also found that the total level of Bcl-2 decreased after HI in vivo and after ionophore challenge in cultured human neuroblastoma (IMR-32) cells in vitro. Furthermore, the Bcl-2 reduction was calpain-dependent, because it could be prevented by the calpain inhibitor CX295 both in vivo and in vitro, suggesting cross-talk between excitotoxic and apoptotic mechanisms.