Loss of lncRNA H19 impairs neonatal cardiac regeneration

Cardiac regeneration represents a major unmet goal in cardiovascular medicine. Although adult mammalian hearts have very limited capacity to regenerate after injury, newborn mouse hearts can fully restore myocardial structure and function following ischemic damage. This remarkable regenerative ability is rapidly lost within the first postnatal week, but the molecular mechanisms remain poorly understood. Long noncoding RNAs (lncRNAs) have emerged as important regulators of tissue repair and regeneration. Therefore, we aimed to identify lncRNAs involved in neonatal cardiac regeneration and to investigate the function of a candidate lncRNA in regenerating mouse hearts. RNA-sequencing of postnatal day 1 (P1) and P7 mouse hearts revealed approximately 700 significantly differentially expressed lncRNAs. Mapping three neonatal heart RNA-sequencing datasets identified the conserved lncRNA H19 as a major nodal point. To assess its potential regenerative function, permanent left anterior descending artery (LAD) ligation surgeries were performed in P1 H19 knockout (KO) and wild-type (WT) mice. Myocardial infarction (MI) induction and cardiac function were evaluated by echocardiography. Hearts were harvested for molecular biological and histopathological analyses. Unlike H19WT mice, H19KO neonates failed to recover cardiac function after MI. Although H19WT hearts showed no fibrotic scarring and complete cardiac regeneration, H19KO hearts exhibited increased collagen and Mmp9 expression 1-wk post-MI and exhibited fibrotic healing at 1 and 2 wk post-MI. In addition, H19KO mice displayed increased proliferation of noncardiomyocytes and altered immune cells when compared with H19WT mice, indicating substantially impaired cardiac regeneration. In conclusion, H19 is essential for complete cardiac regeneration after MI in neonatal mice.NEW & NOTEWORTHY This study highlights the previously unknown role of the conserved lncRNA H19 in cardiac regeneration in neonatal mice. The absence of H19 leads to fibrosis, impaired functional heart recovery, and altered immune and proliferative responses in newborn mice after ischemic cardiac injury. These findings highlight H19 as a promising candidate for improving cardiac regenerative potential and identifying auxiliary factors that aid underlying processes.