Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-Mediated Enhancement of Anabolic Synthesis

• DOI: 10.1161/circulationaha.118.037803
• Publication Date: 2019-01-14T10:01:21Z
• Authors: Hong Ma; Shuo Yu; Xiaojing Liu; Yingao Zhang; Thomas Fakadej; Ziqing Liu; Chaoying Yin; Weining Shen; Jason W. Locasale; Joan M. Taylor; Li Qian; Jiandong Liu
• Keywords: RNA Stability; Messenger; Left; Clinical sciences; Cardiorespiratory Medicine and Haematology; Cardiovascular; Mitochondria, Heart; Ventricular Function, Left; Rats, Sprague-Dawley; Mice; Cardiovascular Medicine and Haematology; 2.1 Biological and endogenous factors; Ventricular Function; Myocytes, Cardiac; Aetiology; Cells, Cultured; Mice, Knockout; 0303 health sciences; Cultured; Ventricular Remodeling; cardiac hypertrophy; RNA-Binding Proteins; Heart; glycolysis; Left Ventricular; Mitochondria; Heart Disease; Public Health and Health Services; Hypertrophy, Left Ventricular; Cardiac; Glycolysis; Protein Binding; Cells; Knockout; Clinical Sciences; Cardiovascular medicine and haematology; Lin28a; 03 medical and health sciences; Health Sciences; Genetics; Animals; RNA, Messenger; Sports Science and Exercise; Cell Proliferation; Myocytes; Biomedical and Clinical Sciences; Animal; Hypertrophy; Rats; Disease Models, Animal; Cardiovascular System & Hematology; Pck2; Disease Models; RNA; Sprague-Dawley; Sports science and exercise; Energy Metabolism; metabolism; Phosphoenolpyruvate Carboxykinase (ATP)

Hypertrophic response to pathological stimuli is a complex biological process that involves transcriptional and epigenetic regulation of the cardiac transcriptome. Although previous studies have implicated factors signaling molecules in hypertrophy, role RNA-binding protein this has received little attention.Here we used transverse aortic constriction vitro hypertrophy models characterize an evolutionary conserved Lin28a hypertrophy. Next-generation sequencing, RNA immunoprecipitation, gene expression analyses were applied identify downstream targets Lin28a. Epistatic analysis, metabolic assays, flux analysis further effects its mediator cardiomyocyte hypertrophic growth remodeling.Cardiac-specific deletion attenuated pressure overload-induced growth, dysfunction, alterations Mechanistically, directly bound mitochondrial phosphoenolpyruvate carboxykinase 2 ( Pck2) mRNA increased transcript level. Increasing Pck2 was sufficient promote similar caused by increasing Lin28a, whereas knocking down norepinephrine-induced demonstrated mediated, at least part, growth. Furthermore, metabolomic highlighted for promoting biosynthesis required cell growth.Our study demonstrates promotes glycolytic reprograming, binding stabilizing mRNA.