Abstract MP239: Hippo Signaling Pathway Maintains Homeostasis Of The Cardiac Conduction System

Abstract

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats. The fundamental Hippo signaling pathway plays critical roles in the heart, yet its role in the CCS remains largely unknown. Here, we found that conditional knockout (CKO) of Hippo signaling kinases Lats1 and Lats2 in the CCS using Hcn4 CreERT2 , led to cardiac arrhythmias in adult mice. Compared with controls, Lats1/2 CKO mutant mice had disrupted calcium homeostasis, increased fibrosis and more fibroblast proliferation in the sinoatrial node. Deletion of the Hippo signaling effectors Yap and Taz in the CCS rescued phenotypes caused by Lats1/2 deletion, and these mice had rescued sinus rhythm and reduced fibrosis, which indicated that Lats1/2 function through Yap and Taz in CCS. Our Cleavage Under Targets and Tagmentation (CUT&Tag)-sequencing using Yap antibody followed by RNA-Seq revealed that Yap directly regulates calcium homeostasis genes such as Ryr2 and fibrosis induction genes such as TGF-β family. Further, we discovered that miR-17-92 represses Hippo signaling by directly suppressing Lats2 expression. miR-17-92 CKO in the CCS led to increased Hippo signaling activity and cardiac arrhythmias, indicating that a fine-tuned level of Hippo signaling is critical for CCS homeostasis. Together, our findings reveal the critical role of a miR-Hippo-Yap genetic pathway in maintaining CCS homeostasis.