Abstract：
Histone deacetylase 9 (HDAC9) is implicated in ischemic stroke by genome-wide association studies. We conducted a series of experiments using a mouse model of ischemic stroke (middle cerebral artery occlusion followed by reperfusion) to examine the potential role of HDAC9. Briefly, HDAC9 was upregulated in the penumbra. Deletion of HDAC9 from neurons reduced infarction volume, inhibited neuronal apoptosis in the penumbra, and improved neurological outcomes. HDAC9 knockout from neurons in the penumbra upregulated cGMP-dependent kinase II (cGK II), blocking which abrogated the protective effects of HDAC9 deletion. Mechanistically, HDAC9 interacts with the transcription factor MEF2, thereby inhibiting MEF2\'s binding to the promoter region of the cGK II gene, which results in the suppression of cGK II expression. Inhibiting the interaction between HDAC9 and MEF2 by BML210 upregulated cGK II and attenuated ischemic injury in mice. These results encourage targeting the HDAC9-MEF2 interaction in developing novel therapy against ischemic stroke.
摘要：
通过全基因组关联研究，组蛋白脱乙酰酶9（HDAC9）与缺血性中风有关。我们使用缺血性中风（大脑中动脉阻塞后再灌注）的小鼠模型进行了一系列实验，以检查HDAC9的潜在作用。简而言之，HDAC9在半影中上调。从神经元中删除HDAC9可减少梗死体积，抑制半影区的神经元凋亡，和改善神经系统的结果。半影上调的cGMP依赖性激酶II（cGKII）中神经元的HDAC9敲除，阻断消除HDAC9缺失的保护作用。机械上,HDAC9与转录因子MEF2相互作用，从而抑制MEF2与cGKII基因启动子区的结合，这导致cGKII表达的抑制。通过BML210抑制HDAC9和MEF2之间的相互作用上调cGKII并减轻小鼠的缺血性损伤。这些结果鼓励在开发针对缺血性中风的新疗法中靶向HDAC9-MEF2相互作用。
