LncRNA-6395 promotes myocardial ischemia-reperfusion injury in mice through increasing p53 pathway
LncRNA-6395 promotes myocardial ischemia-reperfusion injury in mice through increasing p53 pathway
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LncRNA-6395通过增加p53通路促进小鼠心肌缺血再灌注损伤
DOI：
10.1038/s41401-021-00767-5
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发表时间：
2021-09-07
影响因子：
8.2
通讯作者：
Zhang, Ming-yu
中科院分区：
文献类型：
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作者：
Zhan, Lin-feng;Zhang, Qi;Zhang, Ming-yu
心肌缺血再灌注（I/R）损伤是以心肌细胞凋亡为特征的病理过程，导致心功能不全。越来越多的证据表明，长非编码RNA (lncRNA) 的异常表达在心血管疾病中发挥着至关重要的作用。在这项研究中，我们研究了 lncRNA 在心肌 I/R 损伤中的作用。通过结扎左冠状动脉前降支 45 分钟，然后再灌注 24 小时，诱导小鼠心肌 I/R 损伤。我们发现，lncRNA KnowTID_00006395（称为 lncRNA-6395）在 I/R 损伤后小鼠心脏梗塞区域以及 H2O2 处理的新生小鼠心室心肌细胞 (NMVC) 中显着上调。 lncRNA-6395的过表达导致NMVC中细胞凋亡和凋亡相关蛋白的表达变化，而lncRNA-6395的敲低则减弱了H2O2诱导的细胞凋亡。 LncRNA-6395 敲除小鼠 (lncRNA-6395(+/-)) 在 I/R 损伤后表现出心脏功能改善、血浆 LDH 活性降低和梗塞面积减少。我们证明lncRNA-6395直接与p53结合，并通过抑制泛素化介导的p53降解来增加p53蛋白的丰度，从而促进p53易位到细胞核。更重要的是，p53的过表达抵消了lncRNA-6395敲低对心肌细胞凋亡的抑制作用，而p53的敲低则抵消了lncRNA-6395对心肌细胞的凋亡作用。综上所述，lncRNA-6395作为内源性促凋亡因子，通过抑制p53降解和促进亚细胞易位来调节心肌细胞凋亡和心肌缺血再灌注损伤。
Myocardial ischemia-reperfusion (I/R) injury is a pathological process characterized by cardiomyocyte apoptosis, which leads to cardiac dysfunction. Increasing evidence shows that abnormal expression of long noncoding RNAs (lncRNAs) plays a crucial role in cardiovascular diseases. In this study we investigated the role of lncRNAs in myocardial I/R injury. Myocardial I/R injury was induced in mice by ligating left anterior descending coronary artery for 45 min followed by reperfusion for 24 h. We showed that lncRNA KnowTID_00006395, termed lncRNA-6395 was significantly upregulated in the infarct area of mouse hearts following I/R injury as well as in H2O2-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Overexpression of lncRNA-6395 led to cell apoptosis and the expression change of apoptosis-related proteins in NMVCs, whereas knockdown of lncRNA-6395 attenuated H2O2-induced cell apoptosis. LncRNA-6395 knockout mice (lncRNA-6395(+/-)) displayed improved cardiac function, decreased plasma LDH activity and infarct size following I/R injury. We demonstrated that lncRNA-6395 directly bound to p53, and increased the abundance of p53 protein through inhibiting ubiquitination-mediated p53 degradation and thereby facilitated p53 translocation to the nucleus. More importantly, overexpression of p53 canceled the inhibitory effects of lncRNA-6395 knockdown on cardiomyocyte apoptosis, whereas knockdown of p53 counteracted the apoptotic effects of lncRNA-6395 in cardiomyocytes. Taken together, lncRNA-6395 as an endogenous pro-apoptotic factor, regulates cardiomyocyte apoptosis and myocardial I/R injury by inhibiting degradation and promoting sub-cellular translocation of p53.