Abstract 16566: TLR3 Mediates Neonatal Heart Repair and Regeneration Through Glycolysis-Dependent YAP/TAZ Mediated miR-152 Expression
Introduction: The neonatal heart possesses the capability of regenerating and repairing damaged myocardium which is lost when cardiac metabolism switches from predominate glycolysis to oxidative phosphorylation seven days after birth. We observed that TLR3 deficient neonatal hearts exhibit impaired cardiac function and larger infarct size after myocardial infarction (MI). Stimulation of neonatal cardiomyocytes with the TLR3 ligand, poly (I:C) significantly enhances glycolytic capacity. YAP has been reported to regulate cell proliferation and differentiation.
Hypothesis: TLR3 is required for neonatal heart repair and regeneration of damaged myocardium via glycolysis mediated YAP activation.
Methods: Neonatal cardiomyocytes were isolated from one day old mice and treated with poly (I:C) (1μg/ml) for 12-36 hours. One day old of neonatal mice were subjected to MI.
Results: Poly (I:C) treatment: i) significantly enhances glycolytic metabolism; ii) increases YAP/TAZ activation: iii) increases miR-152 expression; iv) suppresses expression of DNMT1 and p27kip1, and v) promotes cardiomyocyte proliferation. However, inhibition of glycolysis with 2-Deoxyglucose (2-DG) prevented poly (I:C)-induced YAP/TAZ activation and miR-152 expression in neonatal cardiomyocytes. Inhibition of YAP/TAZ activation with Verteprofin (VP) abolished poly (I:C) induced miR-152 expression and neonatal cardiomyocyte proliferation. To investigate the role of miR-152 in neonatal cardiomyocyte proliferation, we transfected neonatal cardiomyocytes with miR-152 mimics and observed that increased miR-152 levels significantly promotes neonatal cardiomyocyte proliferation. We also observed that transfection of neonatal cardiomyocytes with miR-152 mimics markedly suppresses the expression of DNMT1 and p27kip1. Inhibition of DNMT1 with 5Azcytidine significantly promotes neonatal cardiomyocyte proliferation. Finally, we observed that treatment of neonatal mice (n=6) with 2-DG abolished cardiac functional recovery 3 weeks after MI.
Conclusions: TLR3 is required for neonatal heart regeneration and repair after MI. The mechanisms involve glycolytic dependent activation of YAP/TAZ mediated by miR-152 which represses DNMT1/p27kip1 expression.
Author Disclosures: X. Wang: None. T. Ha: None. J. Kalbfleisch: None. D. Williams: None. C. Li: None.
- © 2016 by American Heart Association, Inc.