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Long noncoding RNA Meg3 regulates cardiomyocyte apoptosis in myocardial infarction

Abstract

Myocardial infarction (MI), with a major process of cardiomyocyte death, remains a leading cause of morbidity and mortality worldwide. To date, it has been shown that lncRNAs play important roles in cardiovascular pathology. However, the detailed studies on lncRNAs regulating cardiomyocyte death in myocardial infarction are still limited. In this study, we found a progressively upregulated expression of Meg3 in mouse injured heart after MI. Gain-of-function and loss-of-function approaches further revealed pro-apoptotic functions of Meg3 in rodent cardiomyocytes. Moreover, Meg3 was directly upregulated by p53 in hypoxic condition, and involved in apoptotic regulation via its direct binding with RNA-binding protein FUS (fused in sarcoma). Afterwards, adult MI mice that underwent intramyocardial injection with adeno-associated virus serotype 9 (AAV9) system carrying Meg3 shRNA showed a significant improvement of cardiac function. Moreover, we also found that MEG3 was increased in clinical heart failure samples, and had conservatively pro-apoptotic function in human cardiomyocytes that were differentiated from the human embryonic stem cells. Together, these results indicate that p53-induced Meg3–FUS complex plays an important role in cardiomyocyte apoptosis post-MI, and its specific knockdown in cardiomyocytes with AAV9 system represents a promising method to treat MI for preclinical investigation.

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Acknowledgements

This study was supported by National Key R&D Program of China [2017YFA0103700], National Natural Science Foundation of China (NSFC) [91739106, 81500277, 81770257, 81600218], Natural Science Foundation of Jiangsu Province [BK20150320, BK20170002, BK20150321, BK20150345], Suzhou Municipal Science and Technology Foundation [SYS201675, SYS201540], Natural Science Foundation for Colleges and Universities in Jiangsu Province [17KJA310006, 15KJB180017], National Clinical Key Specialty of cardiovascular surgery, Jiangsu Clinical Research Center for Cardiovascular Surgery and Jiangsu Province’s Key Discipline / Laboratory of Medicine [XK201118], and National Center for International Research [2017B01012].

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Correspondence to Shijun Hu.

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Wu, H., Zhao, ZA., Liu, J. et al. Long noncoding RNA Meg3 regulates cardiomyocyte apoptosis in myocardial infarction. Gene Ther 25, 511–523 (2018). https://doi.org/10.1038/s41434-018-0045-4

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