TY - JOUR
T1 - Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction
AU - Cai, Benzhi
AU - Ma, Wenya
AU - Wang, Xiuxiu
AU - Sukhareva, Natalia
AU - Hua, Bingjie
AU - Zhang, Lai
AU - Xu, Juan
AU - Li, Xingda
AU - Li, Shuainan
AU - Liu, Shenzhen
AU - Yu, Meixi
AU - Xu, Yan
AU - Song, Ruijie
AU - Xu, Binbin
AU - Yang, Fan
AU - Han, Zhenbo
AU - Ding, Fengzhi
AU - Huang, Qi
AU - Yu, Ying
AU - Zhao, Yue
AU - Wang, Jin
AU - Bamba, Djibril
AU - Zagidullin, Naufal
AU - Li, Faqian
AU - Tian, Ye
AU - Pan, Zhenwei
AU - Yang, Baofeng
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078136922&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078136922&partnerID=8YFLogxK
U2 - 10.1038/s41418-020-0492-5
DO - 10.1038/s41418-020-0492-5
M3 - Article
C2 - 31969690
AN - SCOPUS:85078136922
SN - 1350-9047
VL - 27
SP - 2158
EP - 2175
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 7
ER -