LncRNA-6395 promotes myocardial ischemia-reperfusion injury in mice through increasing p53 pathway

作者：Zhan, Lin-feng; Zhang, Qi; Zhao, Lu; Dong, Xue; Pei, Xin-yu; Peng, Li-li; Zhang, Xiao-wen; Meng, Bo; Shang, Wen-di; Pan, Zhen-wei; Xu, Chao-qian; Lu, Yan-jie^*; Zhang, Ming-yu^*

来源：Acta Pharmacologica Sinica, 2022, 43(6): 1383-1394.

DOI：10.1038/s41401-021-00767-5

• myocardial I
• R injury
• H2O2
• lncRNA
• apoptosis
• p53
• ubiquitination
• neonatal mouse ventricular cardiomyocytes

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.

• 单位
  哈尔滨医科大学