Estrogen-related receptor gamma induces cardiac hypertrophy by activating GATA4

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• 作者：Duk-Hwa Kwon ; Gwang Hyeon Eom ; Hae Jin Kee ; Yoon Seok Nam ; Young Kuk Cho ; Don-Kyu Kim ; Ja Young Koo ; Hyung-Seok Kim ; Kwang-Il Nam ; Kyung Keun Kim ; In-Kyu Lee ; Seung Bum Park ; Hueng-Sik Choi ; Hyun Kook
• 关键词：Estrogen-related receptor gamma ; Orphan nuclear receptor ; GATA4 ; GSK-5182 ; Cardiac hypertrophy
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：December, 2013
• 年：2013
• 卷：65
• 期：Complete
• 页码：88-97
• 全文大小：2038 K

文摘

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