Department of Cardiology, Renmin Hospital of Wuhan University; Cardiovascular Research Institute, Wuhan University; Hubei Key Laboratory of Cardiology, Wuhan, 430000, China.
Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, 443003, China.
Commun Biol. 2022 Mar 25;5(1):270. doi: 10.1038/s42003-022-03225-y.
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.
我们之前的研究已经描述了组蛋白去甲基酶 KDM3A 在糖尿病血管重构中的作用，但其在心肌缺血/再灌注（I/R）损伤（MIRI）中的作用仍有待阐明。在这里，我们显示 KDM3A 在大鼠 I/R 和细胞缺氧/复氧（H/R）模型中显著下调。随后，进行了增益和失能实验，以研究 KDM3A 在 MIRI 中的作用。KDM3A 敲除在体内和体外均加重了心脏功能障碍和心肌细胞损伤。同时观察到线粒体凋亡、活性氧和炎症的恶化。相反，KDM3A 的过表达改善了 MIRI 的变化。在机制上，KDM3A 通过增强 ETS1 的表达来减轻 MIRI 的影响。ChIP-PCR 证实 KDM3A 结合到 ETS1 启动子上，并去除组蛋白 H3 赖氨酸 9（H3K9me2）的二甲基化，从而促进 ETS1 转录。我们的研究结果表明，KDM3A 通过调节 ETS1 可用于缓解 MIRI 的多种病因。
