Dandan Liang1, Jun Li1, Yahan Wu2, Lixiao Zhen2, Changming Li2, Man Qi2, Lijie Wang2, Fangfei Deng2, Jian Huang2, Fei Lv2, Yi Liu1, Xiue Ma2, Zuoren Yu3, Yuzhen Zhang3, Yi-Han Chen4. 1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Research Center for Translational Medicine, Tongji University School of Medicine, Shanghai 200120, China; Institute of Medical Genetics, Tongji University, Shanghai 200092, China. 2. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China. 3. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Research Center for Translational Medicine, Tongji University School of Medicine, Shanghai 200120, China. 4. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Research Center for Translational Medicine, Tongji University School of Medicine, Shanghai 200120, China; Institute of Medical Genetics, Tongji University, Shanghai 200092, China; Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China. Electronic address: yihanchen@tongji.edu.cn.
Abstract
OBJECTIVES: In mammals, the heart grows by hypertrophy but not proliferation of cardiomyocytes after birth. The paucity of cardiomyocyte proliferation limits cardiac regeneration in a variety of heart diseases. To explore the efficient strategies that drive cardiomyocyte proliferation, we employed in vitro and in vivo models to investigate the function of miRNA-204, which was demonstrated to regulate the proliferation and differentiation of human cardiac progenitor cells in our previous study. METHODS AND RESULTS: miRNA-204 overexpression markedly promoted cardiomyocyte proliferation in both neonatal and adult rat cardiomyocytes in vitro. Transgenic mice with the cardiac-specific overexpression of miRNA-204 exhibited excessive cardiomyocyte proliferation throughout the embryonic and adult stages, leading to a pronounced increase in ventricular mass. Accordingly, the cell cycle regulators, including Cyclin A, Cyclin B, Cyclin D2, Cyclin E, CDC2 and PCNA, were upregulated in miRNA-204 transgenic embryonic hearts. Furthermore, we demonstrated that miRNA-204 directly targeted Jarid2. Knockdown of Jarid2 mimicked the pro-proliferative effect of miRNA-204 overexpression on cultured rat cardiomyocytes, whereas enhanced expression of Jarid2 conferred the myocytes with substantial resistance to proliferation by miRNA-204 overexpression. CONCLUSION: Our findings identify a conserved role for miRNA-204 in regulating cardiomyocyte proliferation by targeting the Jarid2 signaling pathway.
OBJECTIVES: In mammals, the heart grows by hypertrophy but not proliferation of cardiomyocytes after birth. The paucity of cardiomyocyte proliferation limits cardiac regeneration in a variety of heart diseases. To explore the efficient strategies that drive cardiomyocyte proliferation, we employed in vitro and in vivo models to investigate the function of miRNA-204, which was demonstrated to regulate the proliferation and differentiation of human cardiac progenitor cells in our previous study. METHODS AND RESULTS:miRNA-204 overexpression markedly promoted cardiomyocyte proliferation in both neonatal and adult rat cardiomyocytes in vitro. Transgenic mice with the cardiac-specific overexpression of miRNA-204 exhibited excessive cardiomyocyte proliferation throughout the embryonic and adult stages, leading to a pronounced increase in ventricular mass. Accordingly, the cell cycle regulators, including Cyclin A, Cyclin B, Cyclin D2, Cyclin E, CDC2 and PCNA, were upregulated in miRNA-204transgenicembryonic hearts. Furthermore, we demonstrated that miRNA-204 directly targeted Jarid2. Knockdown of Jarid2 mimicked the pro-proliferative effect of miRNA-204 overexpression on cultured rat cardiomyocytes, whereas enhanced expression of Jarid2 conferred the myocytes with substantial resistance to proliferation by miRNA-204 overexpression. CONCLUSION: Our findings identify a conserved role for miRNA-204 in regulating cardiomyocyte proliferation by targeting the Jarid2 signaling pathway.
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