环状RNA ciRS-17-3p下调介导运动诱导的生理性心肌肥大及机制研究

Our findings published in《Theranostics》(Impact factor: 8.854) show that microRNA-17-3p (miR-17-3p) mediates exercise-induced physiological cardiac growth, and protects against cardiac ischemia/reperfusion (I/R) injury. We previously identified a circular RNA (ciRS-17-3p) as a potential sponge for miR-17-3p, and found that ciRS-17-3p was downregulated in physiological cardiac hypertrophy, while not changed in pathological cardiac hypertrophy, indicating that ciRS-17-3p might regulate physiological cardiac growth. In the present project, we will first confirm ciRS-17-3p as a sponge for miR-17-3p. After that, we will perform gain-of-function and loss-of-function experiments in cardiomyocytes and swim mice to clarify the role of ciRS-17-3p in physiological cardiac growth. Next, function-rescue experiments will be performed to elucidate whether miR-17-3p is responsible for the effects of ciRS-17-3p in physiological cardiac growth. Finally, we will investigate whether ciRS-17-3p downregulation could protect against cardiac I/R injury. This project will help identify ciRS-17-3p as a novel therapeutic target mediating the protective effect of exercise in cardiac I/R injury.

我们已发表于《Theranostics》杂志（影响因子：8.854分）的研究发现，微小RNA-17-3p（miR-17-3p）介导运动诱导的生理性心肌肥大，保护心肌缺血再灌注（I/R）损伤。我们在前期鉴定出miR-17-3p潜在的分子海绵——环状RNA ciRS-17-3p在生理性心肌肥大中表达下调，在病理性心肌肥大中表达不变，提示其可能参与调控生理性心肌肥大。在本项目中，拟首先证实ciRS-17-3p是miR-17-3p的分子海绵。接着，基于心肌细胞和游泳小鼠，通过功能获得性和功能缺失性实验，明确ciRS-17-3p与生理性心肌肥大的关系。随后，实施功能逆转实验，明确ciRS-17-3p是否通过miR-17-3p调控生理性心肌肥大。最后，观察下调ciRS-17-3p是否对心肌I/R损伤具有保护效应。本项目将基于ciRS-17-3p为运动诱导生理性心肌肥大防治心肌I/R损伤提供治疗靶点。

本项目组先前报道微小RNA（miR-17-3p）是一个运动诱导生理性心肌肥厚的关键微小RNA，保护心肌细胞抵抗凋亡和缺血再灌注损伤。越来越多的研究表明，运动诱导生理性心肌肥厚的关键分子，具有潜在的阻断病理性心肌肥厚和心力衰竭的作用。本项目旨在探索miR-17-3p在病理性心肌肥厚和心力衰竭中的作用，阐明miR-17-3p发挥心肌保护作用的细胞和分子基础，鉴定并明确环状RNA ciRS-17-3p（即：cZNF521）作为分子海绵调控miR-17-3p及其对心肌细胞的功能。首先，我们基于miR-17-3p全身过表达小鼠，明确了过表达miR-17-3p能够有效地改善主动脉弓缩窄诱导的心功能下降，减轻病理性心肌肥厚和心脏组织纤维化。接着，在新生大鼠心肌细胞水平，采用苯肾上腺素诱导心肌细胞发生病理性肥大，明确过表达miR-17-3p能够抑制心肌细胞的病理性肥大，改善ANP和BNP病理性肥厚标志基因的表达变化。进一步，通过生物信息学分析预测出PTEN可能是miR-17-3p的下游靶基因，通过心肌细胞水平的功能逆转实验，阐明miR-17-3p通过抑制PTEN激活AKT，进而抑制病理性心肌肥厚的分子机制。与此同时，我们采集急性心肌梗死患者首次入院时的血清，揭示了入院血清miR-17-3p低表达是预测急性心肌梗死患者1年后发生死亡或者再入院的独立预测因子。最后，我们鉴定出环状RNA cZNF521可以作为miR-17-3p的分子海绵，在心肌细胞负调控miR-17-3p的表达（将其命名为ciRS-17-3p），并揭示敲低ciRS-17-3p具有促心肌细胞增殖的功能。综上，本项目从运动诱导生理性心肌肥厚的miR-17-3p出发，明确了miR-17-3p在病理性心肌肥厚和心力衰竭中的保护作用及分子机制，并揭示了其上游环状RNA ciRS-17-3p对心肌细胞增殖的功能，ciRS-17-3p是一个潜在的介导运动心肌保护效应的非编码RNA。