Abstract 15973: miRNA-Hippo Pathway Plays a Critical Role in the Cardiac Conduction System

Abstract

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats and the 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 the 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 the CCS. Specific disruption of either miR-17-92 or Hippo signaling in the CCS gave rise to cardiac arrhythmias in mice. Notably, miR-17-92 regulates Hippo signaling through directly 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 antibody, the Hippo signaling effector, which data suggested that Hippo signaling regulates genes involved in the CCS homeostasis. Together, our data indicate a novel miR-Hippo genetic pathway plays critical function in the CCS.