Kun Wang1, Bo Long2, Fang Liu3, Jian-Xun Wang4, Cui-Yun Liu4, Bing Zhao4, Lu-Yu Zhou4, Teng Sun4, Man Wang4, Tao Yu4, Ying Gong4, Jia Liu4, Yan-Han Dong4, Na Li4, Pei-Feng Li1. 1. Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China wangk696@163.com peifengliqd@163.com. 2. Laboratory of Molecular Medicine, Central Research Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100730, China. 3. Department of Anatomy, College of Basic Medicine, Guilin Medical University, Guilin 541004, China. 4. Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
Abstract
AIMS: Sustained cardiac hypertrophy accompanied by maladaptive cardiac remodelling represents an early event in the clinical course leading to heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. However, the molecular mechanisms that regulate cardiac hypertrophy are largely unknown. METHODS AND RESULTS: Here we show that a circular RNA (circRNA), which we term heart-related circRNA (HRCR), acts as an endogenous miR-223 sponge to inhibit cardiac hypertrophy and heart failure. miR-223 transgenic mice developed cardiac hypertrophy and heart failure, whereas miR-223-deficient mice were protected from hypertrophic stimuli, indicating that miR-223 acts as a positive regulator of cardiac hypertrophy. We identified ARC as a miR-223 downstream target to mediate the function of miR-223 in cardiac hypertrophy. Apoptosis repressor with CARD domain transgenic mice showed reduced hypertrophic responses. Further, we found that a circRNA HRCR functions as an endogenous miR-223 sponge to sequester and inhibit miR-223 activity, which resulted in the increase of ARC expression. Heart-related circRNA directly bound to miR-223 in cytoplasm and enforced expression of HRCR in cardiomyocytes and in mice both exhibited attenuated hypertrophic responses. CONCLUSIONS: These findings disclose a novel regulatory pathway that is composed of HRCR, miR-223, and ARC. Modulation of their levels provides an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Sustained cardiac hypertrophy accompanied by maladaptive cardiac remodelling represents an early event in the clinical course leading to heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. However, the molecular mechanisms that regulate cardiac hypertrophy are largely unknown. METHODS AND RESULTS: Here we show that a circular RNA (circRNA), which we term heart-related circRNA (HRCR), acts as an endogenous miR-223 sponge to inhibit cardiac hypertrophy and heart failure. miR-223transgenic mice developed cardiac hypertrophy and heart failure, whereas miR-223-deficient mice were protected from hypertrophic stimuli, indicating that miR-223 acts as a positive regulator of cardiac hypertrophy. We identified ARC as a miR-223 downstream target to mediate the function of miR-223 in cardiac hypertrophy. Apoptosis repressor with CARD domain transgenic mice showed reduced hypertrophic responses. Further, we found that a circRNA HRCR functions as an endogenous miR-223 sponge to sequester and inhibit miR-223 activity, which resulted in the increase of ARC expression. Heart-related circRNA directly bound to miR-223 in cytoplasm and enforced expression of HRCR in cardiomyocytes and in mice both exhibited attenuated hypertrophic responses. CONCLUSIONS: These findings disclose a novel regulatory pathway that is composed of HRCR, miR-223, and ARC. Modulation of their levels provides an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure. Published on behalf of the European Society of Cardiology. All rights reserved.