Sirt1 antisense long noncoding rna promotes cardiomyocyte proliferation by enhancing the stability of sirt1

Abstract

Background—Antisense long noncoding RNAs (lncRNAs) are single-stranded RNAs that overlapped gene-coding regions on the opposite DNA strand and play as critical regulators in cardiovascular diseases. The high conservation and stability may be good advantages for antisense lncRNAs. However, the roles of antisense lncRNAs in cardiomyocyte proliferation and cardiac regeneration are still unknown. Methods and Results-—In this study, we found that Silent information regulator factor 2 related enzyme 1 (Sirt1) antisense lncRNA expression was significantly increased during heart development. By gain and loss function of Sirt1 antisense lncRNA using adenovirus and locked nucleic acid, respectively, we demonstrated that Sirt1 antisense lncRNA promoted cardiomyocyte proliferation in vitro and in vivo, and the suppression of Sirt1 antisense lncRNA inhibited cardiomyocyte proliferation. Moreover, overexpression of Sirt1 antisense lncRNA enhanced cardiomyocyte proliferation, attenuated cardiomyocyte apoptosis, improved cardiac function, and decreased mortality rate after myocardial infarction. Furthermore, Sirt1 antisense lncRNA can bind the Sirt1 30-untranslated region, enhancing the stability of Sirt1 and increasing Sirt1 abundance at both the mRNA and protein levels. Finally, we found that Sirt1 was involved in Sirt1 antisense lncRNA-induced cardiomyocyte proliferation. Conclusions—The present study identified Sirt1 antisense lncRNA as a novel regulator of cardiomyocyte proliferation and cardiac regeneration by interacting and stabilizing Sirt1 mRNA, which may serve as an effective gene target for preventing myocardial infarction. (J Am Heart Assoc. 2018;7:e009700. DOI: 10.1161/JAHA.118.009700.).