The histone demthylase KDM3A protects the myocardium from ischemia/reperfusion injury via promotion of ETS1 expression.
The histone demthylase KDM3A protects the myocardium from ischemia/reperfusion injury via promotion of ETS1 expression.
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组蛋白脱甲基酶 KDM3A 通过促进 ETS1 表达保护心肌免受缺血/再灌注损伤
DOI：
10.1038/s42003-022-03225-y
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发表时间：
2022-03-25
影响因子：
5.9
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Guo X;Zhang BF;Zhang J;Liu G;Hu Q;Chen J
组蛋白去甲基化酶KDM 3A在糖尿病血管重构中的作用已被研究证实，但其在心肌缺血/再灌注损伤（MIRI）中的作用仍有待进一步阐明。在这里，我们表明，KDM 3A在大鼠I/R和细胞缺氧/复氧（H/R）模型中显著下调。随后，进行功能获得和功能丧失实验以研究KDM 3A在MIRI设置中的作用。KDM 3A基因敲除在体内和体外均加重心功能不全和心肌细胞损伤。同时观察到线粒体凋亡、活性氧和炎症反应的恶化。相反，KDM 3A过表达改善了MIRI的变化。从机制上讲，KDM 3A的MIRI缓解作用与ETS 1表达的增强有关。ChIP-PCR证实KDM 3A与ETS 1启动子结合，去除组蛋白H3赖氨酸9（H3 K9 me 2）的二甲基化，从而促进ETS 1的转录。我们的研究结果表明，KDM 3A可通过调节ETS 1来减轻MIRI的多种病因。预防心脏损伤需要对缺血/再灌注（I/R）事件有更深入的机械理解。在这里，作者发现表观遗传修饰剂KDM 3A通过激活基因ETS 1在心肌I/R损伤中起着至关重要的作用，并建议提高KDM 3A表达可能是一种潜在的治疗策略。
Our prior studies have characterized the participation of histone demethylase KDM3A in diabetic vascular remodeling, while its roles in myocardial ischemia/reperfusion (I/R) injury (MIRI) remain to be illustrated. Here we show that KDM3A was significantly downregulated in rat I/R and cellular hypoxia/reoxygenation (H/R) models. Subsequently, gain- and loss-of-function experiments were performed to investigate the effects of KDM3A in the settings of MIRI. KDM3A knockout exacerbated cardiac dysfunction and cardiomyocytes injury both in vivo and in vitro. The deteriorated mitochondrial apoptosis, reactive oxygen species, and inflammation were simultaneously observed. Conversely, KDM3A overexpression developed the ameliorated alternations in MIRI. Mechanistically, the MIRI-alleviating effects of KDM3A were associated with the enhancement of ETS1 expression. ChIP-PCR affirmed that KDM3A bound to the ETS1 promoter and removed dimethylation of histone H3 lysine 9 (H3K9me2), thus promoting ETS1 transcription. Our findings suggest that KDM3A is available for alleviating multi-etiologies of MIRI through the regulation of ETS1. Prevention of cardiac injury requires a deeper mechanistic understanding of ischemia/reperfusion (I/R) episodes. Here, the authors find that the epigenetic modifier KDM3A plays a crucial role in myocardial I/R injury through its activation of the gene ETS1 and suggest boosting KDM3A expression could be a potential treatment strategy.
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