Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction

Benzhi Cai, Wenya Ma, Xiuxiu Wang, Natalia Sukhareva, Bingjie Hua, Lai Zhang, Juan Xu, Xingda Li, Shuainan Li, Shenzhen Liu, Meixi Yu, Yan Xu, Ruijie Song, Binbin Xu, Fan Yang, Zhenbo Han, Fengzhi Ding, Qi Huang, Ying Yu, Yue ZhaoJin Wang, Djibril Bamba, Naufal Zagidullin, Faqian Li, Ye Tian, Zhenwei Pan, Baofeng Yang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Neonatal mammalian heart maintains a transient regeneration capacity after birth, whereas this regeneration ability gradually loses in the postnatal heart. Thus, the reactivation of cardiomyocyte proliferation is emerging as a key strategy for inducing heart regeneration in adults. We have reported that a highly conserved long noncoding RNA (lncRNA) LncDACH1 was overexpressed in the failing hearts. Here, we found that LncDACH1 was gradually upregulated in the postnatal hearts. Cardiac-specific overexpression of LncDACH1 (TG) in mice suppressed neonatal heart regeneration and worsened cardiac function after apical resection. Conversely, in vivo cardiac conditional knockout of LncDACH1 (CKO) and adenovirus-mediated silencing of endogenous LncDACH1 reactivated cardiomyocyte-proliferative potential and promoted heart regeneration after myocardial infarction (MI) in juvenile and adult mice. Mechanistically, LncDACH1 was found to directly bind to protein phosphatase 1 catalytic subunit alpha (PP1A), and in turn, limit its dephosphorylation activity. Consistently, PP1A siRNA or pharmacological blockers of PP1A abrogated cardiomyocyte mitosis induced by LncDACH1 silencing. Furthermore, LncDACH1 enhanced yes-associated protein 1 (YAP1) phosphorylation and reduced its nuclear translocation by binding PP1A. Verteporfin, a YAP1 inhibitor decreased LncDACH1 silencing-induced cardiomyocyte proliferation. In addition, targeting a conserved fragment of LncDACH1 caused cell cycle re-entry of human iPSC-derived cardiomyocytes. Collectively, LncDACH1 governs heart regeneration in postnatal and ischemic hearts via regulating PP1A/YAP1 signal, which confers a novel therapeutic strategy for ischemic heart diseases.

Original languageEnglish (US)
Pages (from-to)2158-2175
Number of pages18
JournalCell Death and Differentiation
Volume27
Issue number7
DOIs
StatePublished - Jul 1 2020

Bibliographical note

Funding Information:
Acknowledgements This work was supported by the National Key R&D Program of China [2017YFC1307403, 2017YFC1307404], the National Natural Science Fund of China [81872857, 81573434, 81870295, and 81730012] and China Postdoctoral Science Foundation [2018M641867].

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Fingerprint Dive into the research topics of 'Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction'. Together they form a unique fingerprint.

Cite this