Targeting LncDACH1 promotes cardiac repair and regeneration after myocardium infarction.

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.