Abstract 071: Estrogen-related Receptor Gamma Induces Cardiac Hypertrophy By Activating Gata4

Abstract

Introduction— Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor that has biological roles mainly in metabolism and it controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. Hypothesis— In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. Here we show that ERRγ provokes cardiac hypertrophy by inducing GATA4 and that its inverse agonist, GSK-5182, prevents cardiac hypertrophy. Methods and Results— The functional roles of ERRγ in association with development of cardiac hypertrophy were examined in primarily cultured cardiomyocytes, in animal models, and in heart samples from human hypertrophic cardiomyopathy patients. ERRγ expression was increased in hearts obtained from human hypertrophic cardiomyopathy patients and in both agonist-induced cellular models and aortic banding-induced animal models of cardiac hypertrophy. Transgenic overexpression in mouse heart as well as forced expression of ERRγ in cardiomyocytes induced hypertrophic phenotypes. Knock-down of ERRγ blocked agonist-induced hypertrophic phenotypes. ERRγ directly bound to the proximal ERR-responsive element in the GATA4 promoter in a sequence-specific manner and thereby induced transcription. ERRγ-induced hypertrophy was blocked by inhibition of GATA4. GSK-5182 completely blocked cardiac hypertrophy in cardiomyocytes. It also prevented aortic banding-induced cardiac hypertrophy and fibrosis in mouse heart. Conclusion— These findings demonstrate a novel ERRγ/GATA4 signal cascade in the development of cardiac hypertrophy and suggest GSK-5182 as a possible therapeutic.