Infarct volume after transient middle cerebral artery occlusion (MCAo) can be reduced by attenuation but not by inactivation of c-Jun action
Infarct volume after transient middle cerebral artery occlusion (MCAo) can be reduced by attenuation but not by inactivation of c-Jun action
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DOI：
10.1016/j.brainres.2007.03.023
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发表时间：
2007-06
期刊：
影响因子：
2.9
通讯作者：
J. Vogel;M. Weigand;A. Behrens;E. Wagner;Marina Schorpp-Kistner;M. Zimmermann;J. Schenkel
中科院分区：
文献类型：
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作者：
J. Vogel;M. Weigand;A. Behrens;E. Wagner;Marina Schorpp-Kistner;M. Zimmermann;J. Schenkel
脑卒中治疗的目的是挽救因缺血损伤而激活的半影组织细胞凋亡。由于c-Jun转录因子在促进细胞凋亡中起着至关重要的作用，抑制其激活可能会减少最终梗死面积，从而增加功能结局。为了验证这一假设，我们使用了四种转基因小鼠系在不同步骤影响c-Jun通路。在短暂性大脑中动脉闭塞90 min和再灌注24 h后，测定条件c-Jun敲除小鼠（cond）的梗死体积和ATF-2-、TUNEL-和裂解caspase -3阳性细胞的数量。c-Jun)、过表达JunB的小鼠（JunBtg）、缺乏c-Jun的磷酸化受体丝氨酸63和73的小鼠（JunAA）以及过表达Bcl-2的小鼠（Bcl-2tg）。气孔导度。与未突变的对照组相比，c-Jun和JunAA小鼠在梗死面积上没有显着差异。相比之下，在仅减弱c-Jun作用（JunBtg和Bcl-2tg）的转基因小鼠中检测到较小的梗死体积。ATF-2、TUNEL、cleaved Caspase-3染色各组间差异无统计学意义。相对于c-Jun功能的降低，c-Jun功能的完全缺失可能通过其他细胞机制得到补偿。因此，我们的数据表明，衰减而不是完全阻断c-Jun的作用似乎更有希望治疗中风。
Stroke therapy aims to save penumbral tissue from apoptosis that is activated in response to the ischemic injury. Since the c-Jun transcription factor plays a crucial role in promoting apoptosis, inhibition of its activation might reduce the final infarct size and thus increase functional outcome. To test this hypothesis we made use of four genetically modified mouse lines influencing the c-Jun pathway at various steps. Upon transient middle cerebral artery occlusion for 90 min and 24 h of reperfusion, infarct volume and number of ATF-2-, TUNEL- and cleaved Caspase-3-positive cells were determined in conditional c-Jun knock-out mice (cond. c-Jun), mice overexpressing JunB (JunBtg), mice lacking the phosphoacceptor serines 63 and 73 of c-Jun (JunAA) and in mice overexpressing Bcl-2 (Bcl-2tg). Cond. c-Jun as well as JunAA mice did not show significant differences in the infarct size when compared to their non-mutant controls. By contrast smaller infarct volumes were detected in transgenic mice merely attenuating c-Jun action (JunBtg and Bcl-2tg). ATF-2, TUNEL or cleaved Caspase-3 staining revealed no significant differences between the experimental groups. A complete lack of functional c-Jun might be compensated by other cellular mechanisms, in contrast to its reduced function. Thus, our data suggest that attenuation rather than a complete block of c-Jun action appears to be more promising for therapy of stroke.