Abstract 12444: Toll-like Receptor 3 is Required for Neonatal Heart Repair and Regeneration Following Myocardial Infarction via Glycolysis Dependent Yap/taz Activation

Abstract

Regenerative therapies for repair of the damaged heart could benefit millions of patients annually. The neonatal heart has the capability of repairing/regenerating damaged myocardium. However, this capability is lost when cardiomyocyte metabolism changes from glycolysis to oxidative phosphorylation, within 7 days after birth. Interestingly, Toll-like receptors (TLRs) are required for somatic cell nuclear reprogramming, which is important for tissue regeneration. The Hippo pathway effector YAP promotes cardiac regeneration. We have reported that TLR ligands can induce protection against myocardial ischemic injury. We hypothesized that TLRs are required for cardiac regeneration in neonatal heart via glycolysis dependent YAP/TAZ activation. To evaluate our hypothesis, myocardial infarction (MI) was induced in one day of wild type (WT) and TLR3 deficient (TLR3 -/- ) neonatal mice (n=5/group). Cardiac function was examined by echocardiography 3 weeks after MI. Cardiomyocyte regeneration and proliferation were examined by histone3 phosphorylation (p-histone3) and EdU incorporation into the cardiomyocytes. In WT neonatal MI mice, cardiac function completely recovered, infarct size was smaller, more p-histone3, EdU was incorporated into the cardiomyocytes, and YAP/TAZ activation was significantly increased following MI. In contrast, TLR3 -/- neonatal hearts showed impaired cardiac function, larger infarct size, less p-histone3 and EdU incorporation and inactivation of YAP/TAZ after MI. To examine whether stimulation of TLR3 will promote glycolysis, cardiomyocytes were isolated from one day old WT neonatal mice and treated with Poly I:C, the TLR3 ligand. Poly I:C treatment significantly increases lactate production, NAD + /NADH ratio, extracellular acidification (ECAR) and YAP/TAZ activation. However, inhibition of glycolysis with 2-Deoxyglucose (2DG) prevented Poly I:C-induced neonatal cardiomyocyte proliferation and regeneration as well as YAP/TAZ activation. In vivo treatment of WT neonatal mice with 2DG (n=6/group) abolished cardiac functional recovery 3 weeks after MI. We conclude that TLR3 is required for neonatal heart regeneration and repair after MI. The mechanisms involve glycolysis dependent activation of YAP/TAZ.