Department of Pathophysiology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, China.
Laboratory of Clinical and Experimental Pathology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, China.
Mol Neurobiol. 2024 Jun;61(6):3369-3383. doi: 10.1007/s12035-023-03808-8. Epub 2023 Nov 22.
Whether epigenetic modifications participate in the cell apoptosis after ischemic stroke remains unclear. Histone 3 tri-methylation at lysine 27 (H3K27me3) is a histone modification that leads to gene silencing and is involved in the pathogenesis of ischemic stroke. Since the expression of many antiapoptotic genes is inhibited in the ischemic brains, here we aimed to offer an epigenetic solution to cell apoptosis after stroke by reversing H3K27me3 levels after ischemia. GSK-126, a specific inhibitor of enhancer of zeste homolog 2 (EZH2), significantly decreased H3K27me3 levels and inhibited middle cerebral artery occlusion (MCAO) induced and oxygen glucose deprivation (OGD) induced cell apoptosis. Moreover, GSK-126 attenuated the apoptosis caused by oxidative stress, excitotoxicity, and excessive inflammatory responses in vitro. The role of H3K27me3 in regulating of the expression of the antiapoptotic molecule B cell lymphoma-2 like 1 (Bcl2l1) explained the antiapoptotic effect of GSK-126. In conclusion, we found that GSK-126 could effectively protect brain cells from apoptosis after cerebral ischemia, and this role of GSK-126 is closely related to an axis that regulates Bcl2l1 expression, beginning with the regulation of EZH2-dependent H3K27me3 modification.
表观遗传修饰是否参与缺血性中风后的细胞凋亡尚不清楚。组蛋白 3 赖氨酸 27 三甲基化（H3K27me3）是一种导致基因沉默的组蛋白修饰，参与缺血性中风的发病机制。由于许多抗细胞凋亡基因在缺血性大脑中受到抑制，因此我们旨在通过逆转缺血后 H3K27me3 水平来提供针对中风后细胞凋亡的表观遗传解决方案。EZH2 的特异性抑制剂 GSK-126 可显著降低 H3K27me3 水平，并抑制大脑中动脉闭塞（MCAO）和氧葡萄糖剥夺（OGD）诱导的细胞凋亡。此外，GSK-126 可减轻体外氧化应激、兴奋性毒性和过度炎症反应引起的细胞凋亡。H3K27me3 调节抗凋亡分子 B 细胞淋巴瘤-2 样 1（Bcl2l1）的表达，解释了 GSK-126 的抗细胞凋亡作用。总之，我们发现 GSK-126 可有效保护脑缺血后的脑细胞免于凋亡，而 GSK-126 的这种作用与调节 Bcl2l1 表达的轴密切相关，该轴从调节 EZH2 依赖性 H3K27me3 修饰开始。
