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

Abstract

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.

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Fig. 1: Increased expression of lncRNA-6395 in I/R injured mouse hearts and H2O2-treated NMVCs.
Fig. 2: Effects of lncRNA-6395 overexpression on NMVC apoptosis.
Fig. 3: Knockdown of lncRNA-6395 rescued cell apoptosis induced by H2O2.
Fig. 4: P53 is a downstream target of lncRNA-6395.
Fig. 5: Overexpression of p53 abolished the inhibitory effects of lncRNA-6395 knockdown on cell apoptosis.
Fig. 6: Knockdown of p53 decreased the pro-apoptotic effects of lncRNA-6395.
Fig. 7: Knockdown of lncRNA-6395 relieved myocardial I/R injury in mouse model.

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Acknowledgements

The work was supported partly by the National Natural Science Foundation of China (No. 81872871, 82073844, 82070283), Postdoctoral Science Foundation of China (2021T140172) and National Science and Technology Major Project (2018ZX10101003-003-003).

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MYZ, YJL, ZWP, and CQX designed and supervised this study; LFZ, QZ, LZ, XD, and XWZ performed the cell experiments; XYP, LLP, BM, and WDS performed the animal experiments; LFZ, Q,Z and LZ performed the statistical analysis; YJL, MYZ, LFZ and QZ wrote the manuscript; All authors contributed to manuscript revision, and read and approved the submitted version.

Corresponding authors

Correspondence to Yan-jie Lu or Ming-yu Zhang.

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The authors declare no competing interests.

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Cite this article

Zhan, Lf., Zhang, Q., Zhao, L. et al. LncRNA-6395 promotes myocardial ischemia-reperfusion injury in mice through increasing p53 pathway. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00767-5

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Keywords

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

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