The Long Noncoding RNA Hotair Regulates Oxidative Stress and Cardiac Myocyte Apoptosis during Ischemia-Reperfusion Injury
The Long Noncoding RNA Hotair Regulates Oxidative Stress and Cardiac Myocyte Apoptosis during Ischemia-Reperfusion Injury
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长非编码RNA Hotair调节缺血再灌注损伤期间的氧化应激和心肌细胞凋亡
DOI：
10.1155/2020/1645249
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发表时间：
2020-03-12
影响因子：
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通讯作者：
Peng, Yu-Dong
中科院分区：
文献类型：
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作者：
Meng, Kai;Jiao, Jiao;Peng, Yu-Dong
氧化应激和随后的心肌细胞凋亡在心肌缺血-再灌注（I/R）损伤的发生和发展中起着重要作用。同源异型盒转录反义基因间RNA（Hotair）与多种心脏疾病有关，但其在心肌I/R损伤中的作用尚未明确。心脏限制性敲低或过表达Hotair的小鼠暴露于I/R手术。体外培养H9 c2细胞并进行缺氧/复氧（H/R）刺激，以进一步验证Hotair的作用和潜在机制。组织学检查，分子检测，并在体内和体外的功能参数进行了测定。响应于I/R或H/R处理，Hotair表达以含溴结构域蛋白4依赖性方式增加。心脏限制性敲除Hotair加剧，而Hotair过表达阻止I/R诱导的氧化应激，心肌细胞凋亡和心功能障碍。从机制上讲，我们观察到Hotair通过激活AMP活化蛋白激酶α（AMPKα）发挥其有益作用。进一步检测发现Hotair通过调节zeste homolog 2/microRNA-451/钙结合蛋白39（EZH 2/miR-451/Cab 39）轴激活AMPKα。我们提供的证据表明，内源性lncRNA Hotair是心肌I/R损伤中氧化应激和心肌细胞凋亡的重要负性调节剂，其依赖于AMPKα通过EZH 2/miR-451/Cab 39轴激活。
Oxidative stress and subsequent cardiac myocyte apoptosis play central roles in the initiation and progression of myocardial ischemia-reperfusion (I/R) injury. Homeobox transcript antisense intergenic RNA (Hotair) was previously implicated in various heart diseases, yet its role in myocardial I/R injury has not been clearly demonstrated. Mice with cardiac-restricted knockdown or overexpression of Hotair were exposed to I/R surgery. H9c2 cells were cultured and subjected to hypoxia/reoxygenation (H/R) stimulation to further verify the role and underlying mechanisms of Hotair in vitro. Histological examination, molecular detection, and functional parameters were determined in vivo and in vitro. In response to I/R or H/R treatment, Hotair expression was increased in a bromodomain-containing protein 4-dependent manner. Cardiac-restricted knockdown of Hotair exacerbated, whereas Hotair overexpression prevented I/R-induced oxidative stress, cardiac myocyte apoptosis, and cardiac dysfunction. Mechanistically, we observed that Hotair exerted its beneficial effects via activating AMP-activated protein kinase alpha (AMPKα). Further detection revealed that Hotair activated AMPKα through regulating the enhancer of zeste homolog 2/microRNA-451/calcium-binding protein 39 (EZH2/miR-451/Cab39) axis. We provide the evidence that endogenous lncRNA Hotair is an essential negative regulator for oxidative stress and cardiac myocyte apoptosis in myocardial I/R injury, which is dependent on AMPKα activation via the EZH2/miR-451/Cab39 axis.