Kdm6A 通过去甲基化 Ncx 基因的 H3K27me3 来保护心肌细胞免受缺氧诱导的凋亡。
Kdm6A Protects Against Hypoxia-Induced Cardiomyocyte Apoptosis via H3K27me3 Demethylation of Ncx Gene.
机构信息
Department of Cardiology, Beijing Anzhen Hospital Affiliated to Capital Medical University, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
Department of Echocardiography, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.
出版信息
J Cardiovasc Transl Res. 2019 Oct;12(5):488-495. doi: 10.1007/s12265-019-09882-5. Epub 2019 Mar 18.
Molecular events involved in acute myocardial infarction (AMI) still remain unclear. A rat AMI model and cardiomyocytes cultured in vitro were used to mimic hypoxic conditions, and the profiles of histone methylation-related gene expression were explored. The demethylase Kdm6a expression was significantly upregulated in the rat AMI model and in hypoxia induction. The apoptosis rate of cardiomyocytes was significantly exacerbated when Kdm6a was knocked down. The expression of the Na/Ca exchanger (Ncx) was significantly upregulated in cardiomyocytes under hypoxia. Knockdown of Kdm6a downregulated the Ncx expression via enhancing H3K27me3 modification on Ncx gene promoter, and attenuated the intracellular calcium influx ability in cardiomyocytes as a consequence. Kdm6a regulates Ncx expression through reducing the H3K27me3 level on the Ncx promoter or enhancer. This finding provides a basis for further study of Kdm6a as a new regulator for AMI development.
急性心肌梗死（AMI）中涉及的分子事件仍不清楚。本研究采用大鼠 AMI 模型和体外培养的心肌细胞来模拟缺氧条件，探讨组蛋白甲基化相关基因表达谱。在大鼠 AMI 模型和缺氧诱导中，去甲基化酶 Kdm6a 的表达显著上调。当 Kdm6a 被敲低时，心肌细胞的凋亡率显著加剧。在缺氧条件下，心肌细胞中的钠/钙交换器（Ncx）表达显著上调。敲低 Kdm6a 通过增强 Ncx 基因启动子上的 H3K27me3 修饰，下调 Ncx 的表达，从而减弱心肌细胞内的钙内流能力。Kdm6a 通过降低 Ncx 启动子或增强子上的 H3K27me3 水平来调节 Ncx 的表达。这一发现为进一步研究 Kdm6a 作为 AMI 发展的新调节剂提供了依据。
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