环状RNA circ-ECHR介导运动诱导的生理性心肌肥厚的作用及其意义

Exercise can induce physiological cardiac growth and protect heart failure. The role of circular RNAs (circRNAs) in physiological cardiac growth is unclear. We previously generated RNA sequencing data from exercise induced physiological cardiac growth hearts and controls, and detected at least 12000 circRNA candidates. We further characterized one abundant and conserved circRNA_10681, termed Exercise induced Cardiac Hypertrophy related-circular RNA(circ-ECHR). Circ-ECHR was upregulated in exercise induced physiological cardiac growth, while was not changed in pathological cardiac growth. Circ-ECHR knockdown could decrease cardiomyocytes size and inhibit cardiomyocytes proliferation, indicating that circ-ECHR might regulate physiological cardiac growth. In addition, miR-141-5p was identified as a downstream target of circ-ECHR. In this project, we firstly aim to perform circ-ECHR gain- and loss-of-function assays based on cardiomyocytes and swim mice to clarify the role of circ-ECHR in physiological cardiac growth. Secondly, whether circ-ECHR regulates physiological cardiac growth via targeting miR-141-5p will be elucidated by conducting functional rescue assays. Finally, we will investigate whether elevated circ-ECHR could protect against adverse ventricular remodeling and heart failure induced by cardiac ischemia/reperfusion injury in vivo. Our project will identify a critical circRNA contributing to exercise induced physiological cardiac growth and provide a novel therapeutic strategy for heart failure.

运动可诱导生理性心肌肥厚防治心力衰竭。环状RNA在生理性心肌肥厚中的作用尚不清楚。我们前期对游泳小鼠心脏进行环状RNA测序，筛选到一个保守的环状RNA circRNA_10681（命名为circ-ECHR）。Circ-ECHR在生理性心肌肥厚显著升高，在病理性心肌肥厚不变，干扰circ-ECHR会减小心肌细胞面积和抑制其增殖，提示其可能参与调控生理性心肌肥厚。我们鉴定出miR-141-5p是circ-ECHR的潜在下游分子。本项目拟在细胞和动物整体水平进行功能获得性和缺失性实验，明确circ-ECHR与生理性心肌肥厚的关系。然后通过功能逆转实验，明确circ-ECHR是否通过miR-141-5p调控生理性心肌肥厚。最后，探索circ-ECHR上调是否可以防治缺血再灌注损伤所致的心室重构和心力衰竭。本研究将鉴定出一个介导运动诱导的生理性心肌肥厚的关键环状RNA，为心力衰竭的干预提供新靶点。

运动锻炼可以诱导心脏发生生理性心肌肥厚。介导运动诱导生理性心肌肥厚的关键分子具有促进心肌细胞肥大、增殖和抵抗凋亡的效应，根据它们在生理性心肌肥厚中的变化增强/减弱这些分子往往对心室重构和心力衰竭具有保护效应。在本项目中，我们基于C57BL/6J小鼠、新生小鼠心肌细胞、人胚胎干细胞诱导分化的心肌细胞，通过建立动物水平小鼠游泳诱导生理性心肌肥厚模型、小鼠心肌缺血再灌注损伤模型、氧葡萄糖剥夺恢复诱导心肌细胞凋亡模型等，研究了介导生理性心肌肥厚发生的关键环状RNA circ-ECHR在细胞水平和动物水平的功能及作用机制。通过本项目研究发现，circ-ECHR增加是运动诱导生理性心肌肥厚所必需的环状RNA，抑制circ-ECHR会抑制游泳运动诱导生理性心肌肥厚的发生。在细胞水平，circ-ECHR能够调控心肌细胞增殖、肥大和氧葡萄糖剥夺恢复实验诱导所致的心肌细胞凋亡；过表达circ-ECHR能够促进心肌细胞面积增大、增殖增加以及抵抗氧葡萄糖剥夺恢复诱导所致的心肌细胞凋亡。进一步的机制研究表明，circ-ECHR通过蛋白磷酸酶PP5激活Rafl/MAPK/ERK信号通路介导对心肌细胞的调控功能。动物水平，通过尾静脉注射circ-ECHR过表达腺相关病毒9过表达circ-ECHR能够保护缺血再灌注损伤所致的病理性心室重构和心力衰竭。本项目鉴定出了一个介导运动诱导的生理性心肌肥厚的关键环状RNA circ-ECHR，并阐明了circ-ECHR在心肌细胞和心脏中的功能，增加circ-ECHR有望成为治疗心力衰竭的新策略。