Abstract 341: Disturbance of p53-indcued Long Noncoding RNA Meg3 - FUS Complex by AAV9 System Preserves Heart Function in Myocardial Infarction

Abstract

Introduction: The injured heart undergoes a major process of cellular apoptosis in the initial stage of MI, therefore, the most fundamental method to prevent post-MI remodeling is to suppress cardiomyocyte apoptosis. In this study, we have illustrated the key role of long noncoding RNA, Maternally expressed gene 3 ( Meg3 ), on cardiomyocyte apoptosis and the underlying mechanisms in heart. Methods: Neonatal murine cardiomyocytes and human ESC-derived cardiomyocytes were subjected to hypoxia, and cellular apoptosis was evaluated with Annexin V assay. The Meg3 regulation by p53 was measured by luciferase reporter assay. The complex of Meg3 and RNA-binding protein FUS (Fused in sarcoma) was determined by EMSA and RIP. Adeno-Associated Virus serotype 9 (AAV9) system was employed to knock down Meg3 in cardiomyocytes in vivo, and the cardiac function was evaluated by echocardiography and ex-vivo assays. Results: We first found that Meg3 was progressively upregulated in the murine injured heart after MI, and it showed the pro-apoptotic functions in primary cardiomyocytes. Meg3 could be directly upregulated by p53 during hypoxia condition, and was involved in apoptotic regulation via its direct binding with FUS. The Meg3 knockdown in cardiomyocytes by AAV9 system could preserve heart function in murine myocardial infarction. Moreover, its pro-apoptotic function was conserved in human cardiomyocytes. Conclusion: Together, these results indicate that p53-induced Meg3 - FUS complex plays an important role on cardiomyocyte apoptosis post-MI, and its specific knockdown in cardiomyocytes with AAV9 system represents a promising method to treat myocardial infarction.