Abstract 214: A Microrna-hippo Pathway Functions in Cardiac Conduction System Homeostasis and Regeneration

Abstract

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats. CCS defects can give rise to cardiac arrhythmia, a leading cause for morbidity worldwide. Hippo signaling, a known organ size and growth regulator, has recently been shown to inhibit cardiomyocyte proliferation and renewal. However, the role for Hippo signaling in the CCS is unknown. Here, we found that adult mice display cardiac arrhythmias when Hippo signaling is specifically disrupted in the CCS, indicating an important role for Hippo in maintaining CCS homeostasis. We discovered that miR-17-92 represses Hippo signaling by directly repressing Lats2 , a core Hippo pathway component and that Hippo activity is increased in miR-17-92 deleted hearts. Importantly, disruption of miR-17-92 in the CCS gives rise to cardiac arrhythmias in adult mice. Notably, specific injury of the CCS causes severe lethal cardiac arrhythmias, whereas inactivation of Lats efficiently rescues the phenotype. In addition, based on data from the chromatin immunoprecipitation deep sequencing with an antibody against the Hippo signaling effector Yap, we found that Hippo signaling regulates genes involved in the CCS homeostasis and regeneration. Together, our findings indicate that maintenance of CCS homeostasis requires proper levels of Hippo signaling, and that repression of Hippo signaling protects the hearts from CCS damage and subsequent arrhythmogenesis.