The Long Noncoding RNA CAREL Controls Cardiac Regeneration

Benzhi Cai, Wenya Ma, Fengzhi Ding, Lai Zhang, Qi Huang, Xiuxiu Wang, Bingjie Hua, Juan Xu, Jiamin Li, Chongwei Bi, Shuyuan Guo, Fan Yang, Zhenbo Han, Yuan Li, Gege Yan, Ying Yu, Zhengyi Bao, Meixi Yu, Faqian Li, Ye TianZhenwei Pan, Baofeng Yang

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Background: Adult mammalian heart loses regeneration ability following ischemic injury due to the loss of cardiomyocyte mitosis. However, the molecular mechanisms underlying the post-mitotic nature of cardiomyocytes remain largely unknown. Objectives: The purpose of this study was to define the essential role of long noncoding ribonucleic acids (lncRNAs) in heart regeneration during postnatal and adult injury. Methods: Myh6-driving cardiomyocyte-specific lncRNA-CAREL transgenic mice and adenovirus-mediated in vivo silencing of endogenous CAREL were used in this study. The effect of CAREL on cardiomyocyte replication and heart regeneration after apical resection or myocardial infarction was assessed by detecting mitosis and cytokinesis. Results: An lncRNA CAREL was found significantly up-regulated in cardiomyocytes from neonatal mice (P7) in parallel with loss of regenerative capacity. Cardiac-specific overexpression of CAREL in mice reduced cardiomyocyte division and proliferation and blunted neonatal heart regeneration after injury. Conversely, silencing of CAREL in vivo markedly promoted cardiac regeneration and improved heart functions after myocardial infarction in neonatal and adult mice. CAREL acted as a competing endogenous ribonucleic acid for miR-296 to derepress the expression of Trp53inp1 and Itm2a, the target genes of miR-296. Consistently, overexpression of miR-296 significantly increased cardiomyocyte replication and cardiac regeneration after injury. Decline of cardiac regenerative ability in CAREL transgenic mice was also rescued by miR-296. A short fragment containing the conserved sequence of CAREL reduced the proliferation of human induced pluripotent stem cell-derived cardiomyocytes as the full-length CAREL. Conclusions: LncRNA CAREL regulates cardiomyocyte proliferation and heart regeneration in postnatal and adult heart after injury by acting as a competing endogenous ribonucleic acid on miR-296 that targets Trp53inp1 and Itm2a.

Original languageEnglish (US)
Pages (from-to)534-550
Number of pages17
JournalJournal of the American College of Cardiology
Volume72
Issue number5
DOIs
StatePublished - Jul 31 2018

Bibliographical note

Funding Information:
This work was supported by the National Key R&D Program of China (2017YFC1307403), the National Natural Science Fund of China (81573434/81170096/81730012), and the Program for New Century Excellent Talents in Heilongjiang Provincial University (1252-NCET-013). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Publisher Copyright:
© 2018 American College of Cardiology Foundation

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • cardiomyocyte proliferation
  • heart regeneration
  • lncRNA
  • microRNA
  • mitosis
  • myocardial infarction

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