Abstract 415: Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-mediated Enhancement of Anabolic Synthesis

Abstract

During pathological hypertrophy, the heart undergoes extensive metabolic changes prior to the onset of structural remodeling, yet, it remains unknown whether and how this metabolic remodeling could contribute to cardiac hypertrophic growth. Here, we identified the RNA-binding protein Lin28a as a critical regulator of pathological cardiac hypertrophy and metabolic re-patterning. Cardiac specific deletion of Lin28a attenuated pressure overload-induced hypertrophy and cardiac dysfunction. Transcriptomics and metabolomic analysis highlighted roles for Lin28a in promoting cardiac glycolysis and anabolic biosynthesis. Mechanistically, Lin28a directly bound to mitochondrial phosphoenolpyruvate carboxykinase 2 ( Pck2 ) mRNA and positively modulated its transcript level. By utilizing the neonatal rat cardiomyocytes (NRCMs) hypertrophy model, we found that manipulation of Pck2 expression phenocopied the metabolic and hypertrophic phenotypes of manipulating Lin28a expression. Furthermore, epistatic analyses demonstrated that overexpression of Pck2 reversed the attenuation of norepinephrine-induced enhancement of cardiac glycolysis and cardiac hypertrophy by loss of Lin28a function, and knockdown of Pck2 suppressed Lin28a-induced increase in cardiac glycolysis and cardiomyocyte hypertrophic growth. Thus, our study revealed a critical role of Lin28a in the regulation of pathological cardiac hypertrophic growth through Pck2-mediated regulation of cardiac metabolism.