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Histone deacetylase HDAC4 participates in the pathological process of myocardial ischemia-reperfusion injury via MEKK1/JNK pathway by binding to miR-206
Cell Death Discovery ( IF 7 ) Pub Date : 2021-09-15 , DOI: 10.1038/s41420-021-00601-1
Qingman Li 1, 2 , Lijie Zhu 1, 2 , Fangqing Niu 1, 2 , Qingmin Li 1, 2 , Che Wang 1, 2 , Honghui Yang 1, 2 , Chuanyu Gao 1, 2
Affiliation  

Histone deacetylases (HDACs) and microRNAs (miRs) have been reported to exert pivotal roles on the pathogenesis of myocardial ischemia-reperfusion injury (MIRI). Therefore, the present study was performed to define the underlying role of HDAC4 and miR-206 in the pathological process of MIRI. An IRI rat model was established. The interaction between HDAC4 and the promoter region of miR-206 was determined using ChIP, and that between miR-206 and mitogen-activated protein kinase kinase kinase 1 (MEKK1) was determined using dual luciferase reporter gene assay. After the loss- or gain-of-function assay in cardiomyocytes, western blot analysis, RT-qPCR, TUNEL, and ELISA assay were performed to define the roles of HDAC4, miR-206, and MEKK1. Up-regulation of HDAC4 and down-regulation of miR-206 occurred in rat myocardial tissues and cardiomyocytes in MIRI. HDAC4 down-regulation or miR-206 up-regulation contributed to reduced cell apoptosis and the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA), while elevating the superoxide dismutase (SOD) and glutathione (GSH) contents. Meanwhile, HDAC4 silencing promoted the expression of miR-206, which targeted and negatively regulated MEKK1. Then inhibition of JNK phosphorylation reduced the cardiomyocyte apoptosis to alleviate MIRI. Coherently, HDAC4 silencing could up-regulate the expression of miR-206 to reduce cardiomyocyte apoptosis and inhibit oxidative stress, and exerting a protective effect on MIRI via the MEKK1/JNK pathway.



中文翻译:

组蛋白去乙酰化酶HDAC4通过MEKK1/JNK通路与miR-206结合参与心肌缺血再灌注损伤的病理过程

据报道,组蛋白去乙酰化酶 (HDAC) 和微 RNA (miR) 在心肌缺血再灌注损伤 (MIRI) 的发病机制中发挥关键作用。因此,本研究旨在确定 HDAC4 和 miR-206 在 MIRI 病理过程中的潜在作用。建立IRI大鼠模型。HDAC4 与 miR-206 启动子区域之间的相互作用使用 ChIP 测定,miR-206 与丝裂原活化蛋白激酶激酶激酶 1 (MEKK1) 之间的相互作用使用双荧光素酶报告基因测定测定。在心肌细胞中进行功能丧失或获得功能测定后,进行蛋白质印迹分析、RT-qPCR、TUNEL 和 ELISA 测定以确定 HDAC4、miR-206 和 MEKK1 的作用。在 MIRI 的大鼠心肌组织和心肌细胞中发生 HDAC4 上调和 miR-206 下调。HDAC4 下调或 miR-206 上调有助于减少细胞凋亡和肿瘤坏死因子-α (TNF-α)、白细胞介素-6 (IL-6) 和丙二醛 (MDA) 的水平,同时提高超氧化物歧化酶 (SOD) 和谷胱甘肽 (GSH) 含量。同时,HDAC4 沉默促进了 miR-206 的表达,miR-206 靶向并负调控 MEKK1。然后抑制JNK磷酸化减少心肌细胞凋亡以减轻MIRI。一致地,HDAC4 沉默可以上调 miR-206 的表达以减少心肌细胞凋亡和抑制氧化应激,并通过 MEKK1/JNK 途径对 MIRI 发挥保护作用。和丙二醛 (MDA),同时提高超氧化物歧化酶 (SOD) 和谷胱甘肽 (GSH) 的含量。同时,HDAC4 沉默促进了 miR-206 的表达,miR-206 靶向并负调控 MEKK1。然后抑制JNK磷酸化减少心肌细胞凋亡以减轻MIRI。一致地,HDAC4 沉默可以上调 miR-206 的表达以减少心肌细胞凋亡和抑制氧化应激,并通过 MEKK1/JNK 途径对 MIRI 发挥保护作用。和丙二醛 (MDA),同时提高超氧化物歧化酶 (SOD) 和谷胱甘肽 (GSH) 的含量。同时,HDAC4 沉默促进了 miR-206 的表达,miR-206 靶向并负调控 MEKK1。然后抑制JNK磷酸化减少心肌细胞凋亡以减轻MIRI。一致地,HDAC4 沉默可以上调 miR-206 的表达以减少心肌细胞凋亡和抑制氧化应激,并通过 MEKK1/JNK 途径对 MIRI 发挥保护作用。

更新日期:2021-09-15
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