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 Zhao; Jin Wang; Djibril Bamba; Naufal Zagidullin; Faqian Li; Ye Tian; Zhenwei Pan; Baofeng Yang

doi:10.1038/s41418-020-0492-5

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

Laboratory Medicine and Pathology

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22 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 language	English (US)
Pages (from-to)	2158-2175
Number of pages	18
Journal	Cell Death and Differentiation
Volume	27
Issue number	7
DOIs	https://doi.org/10.1038/s41418-020-0492-5
State	Published - 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].

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© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

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Journal Article
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10.1038/s41418-020-0492-5

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Cai, B., Ma, W., Wang, X., Sukhareva, N., Hua, B., Zhang, L., Xu, J., Li, X., Li, S., Liu, S., Yu, M., Xu, Y., Song, R., Xu, B., Yang, F., Han, Z., Ding, F., Huang, Q., Yu, Y., ... Yang, B. (2020). Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction. Cell Death and Differentiation, 27(7), 2158-2175. https://doi.org/10.1038/s41418-020-0492-5

Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction. / Cai, Benzhi; Ma, Wenya; Wang, Xiuxiu; Sukhareva, Natalia; Hua, Bingjie; Zhang, Lai; Xu, Juan; Li, Xingda; Li, Shuainan; Liu, Shenzhen; Yu, Meixi; Xu, Yan; Song, Ruijie; Xu, Binbin; Yang, Fan; Han, Zhenbo; Ding, Fengzhi; Huang, Qi; Yu, Ying; Zhao, Yue; Wang, Jin; Bamba, Djibril; Zagidullin, Naufal; Li, Faqian; Tian, Ye; Pan, Zhenwei; Yang, Baofeng.

In: Cell Death and Differentiation, Vol. 27, No. 7, 01.07.2020, p. 2158-2175.

Research output: Contribution to journal › Article › peer-review

Cai, B, Ma, W, Wang, X, Sukhareva, N, Hua, B, Zhang, L, Xu, J, Li, X, Li, S, Liu, S, Yu, M, Xu, Y, Song, R, Xu, B, Yang, F, Han, Z, Ding, F, Huang, Q, Yu, Y, Zhao, Y, Wang, J, Bamba, D, Zagidullin, N, Li, F, Tian, Y, Pan, Z & Yang, B 2020, 'Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction', Cell Death and Differentiation, vol. 27, no. 7, pp. 2158-2175. https://doi.org/10.1038/s41418-020-0492-5

Cai, Benzhi ; Ma, Wenya ; Wang, Xiuxiu ; Sukhareva, Natalia ; Hua, Bingjie ; Zhang, Lai ; Xu, Juan ; Li, Xingda ; Li, Shuainan ; Liu, Shenzhen ; Yu, Meixi ; Xu, Yan ; Song, Ruijie ; Xu, Binbin ; Yang, Fan ; Han, Zhenbo ; Ding, Fengzhi ; Huang, Qi ; Yu, Ying ; Zhao, Yue ; Wang, Jin ; Bamba, Djibril ; Zagidullin, Naufal ; Li, Faqian ; Tian, Ye ; Pan, Zhenwei ; Yang, Baofeng. / Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction. In: Cell Death and Differentiation. 2020 ; Vol. 27, No. 7. pp. 2158-2175.

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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.",

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

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]. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.",

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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 - 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]. 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.

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Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction

Abstract

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