Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction
Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction
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靶向 LncDACH1 可促进心肌梗死后的心脏修复和再生。
DOI：
10.1038/s41418-020-0492-5
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发表时间：
2020-01-22
影响因子：
12.4
通讯作者：
Yang, Baofeng
中科院分区：
文献类型：
--
作者：
Cai, Benzhi;Ma, Wenya;Yang, Baofeng
新生哺乳动物的心脏在出生后保持着短暂的再生能力，而这种再生能力在出生后的心脏中逐渐丧失。因此，重新激活心肌细胞增殖正在成为诱导成人心脏再生的关键策略。我们已经报道了一个高度保守的长非编码RNA(LncRNA)LncDACH1在衰竭的心脏中过表达。在这里，我们发现LncDACH1在出生后的心脏中逐渐上调。心脏特异的LncDACH1(TG)在小鼠体内的过表达抑制了新生心脏的再生，并使心尖切除后的心功能恶化。相反，在体内，心脏条件基因敲除LncDACH1(CKO)和腺病毒介导的内源性LncDACH1沉默重新激活了心肌细胞增殖能力，并促进了心肌梗死(MI)后的心脏再生。从机制上讲，LncDACH1直接与蛋白磷酸酶1催化亚基α(PP1A)结合，进而限制其去磷酸化活性。PP1AsiRNA或PP1A药理阻断剂可抑制LncDACH1沉默诱导的心肌细胞有丝分裂。此外，LncDACH1通过与PP1A结合，增强YAP1的磷酸化，减少其核转位。YAP1抑制剂维替普芬可抑制LncDACH1沉默诱导的心肌细胞增殖。此外，靶向LncDACH1的保守片段可导致人IPSC来源的心肌细胞重新进入细胞周期。总之，LncDACH1通过调节PP1A/YAP1信号来调控出生后和缺血心脏的心脏再生，这为缺血性心脏病的治疗提供了一种新的策略。
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.