Abstract 260: A miRNA-Hippo Pathway Promotes Cardiac Conduction System Regeneration

Abstract

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats and CCS defects can give rise to cardiac arrhythmia, a leading cause for morbidity worldwide. Given the poor self-repair potential in the adult human CCS, it is critical to elucidate the molecular mechanisms limiting CCS regeneration to facilitate developing efficient cardiovascular therapies. microRNAs (miRs) are small non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster can induce cardiomyocyte proliferation and regeneration. Hippo signaling, an ancient organ size control pathway, represses cardiomyocyte proliferation and regeneration. Here we found that both miR-17-92 and Hippo signaling were active in CCS. Disruption of either miR-17-92 or Hippo signaling in heart gave rise to cardiac arrhythmias in mice. Notably, miR-17-92 regulates Hippo signaling through repressing Lats2, a core Hippo pathway component. In miR-17-92 null mutant hearts, up-regulated Lats2 led to increased Hippo pathway activity. Moreover, we performed chromatin immunoprecipitation deep sequencing (ChIP-Seq) using YAP, the Hippo signaling effector, which suggested that Hippo signaling regulates genes involved in CCS homeostasis. Together, we propose a novel miR-Hippo genetic pathway that promotes CCS regeneration.