Lin Haoran, Bei Yun, Shen Zexu, Wei Taofeng, Ge Yuyang, Yu Lingyan, Xu Huimin, He Wei, Dai Yunjian, Yao Difei, Dai Haibin
Department of Pharmacy, the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Transl Stroke Res. 2025 Jun;16(3):868-881. doi: 10.1007/s12975-024-01272-7. Epub 2024 Jun 28.
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.
全基因组关联研究表明组蛋白去乙酰化酶9（HDAC9）与缺血性中风有关。我们使用缺血性中风小鼠模型（大脑中动脉闭塞后再灌注）进行了一系列实验，以研究HDAC9的潜在作用。简而言之，HDAC9在半暗带中上调。从神经元中删除HDAC9可减少梗死体积，抑制半暗带中的神经元凋亡，并改善神经功能结局。半暗带神经元中的HDAC9基因敲除上调了环磷酸鸟苷依赖性蛋白激酶II（cGK II），阻断该蛋白可消除HDAC9缺失的保护作用。从机制上讲，HDAC9与转录因子MEF2相互作用，从而抑制MEF2与cGK II基因启动子区域的结合，导致cGK II表达受到抑制。用BML210抑制HDAC9与MEF2之间的相互作用可上调cGK II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。
