环状RNA3792保护心肌抵抗缺血/再灌注损伤的作用和机制研究

Effectively reducing ischemia/reperfusion (I/R) injury is a key issue in the treatment of ischemic heart disease, but the efficiency of the approaches is limited. One important reason is that the mechanisms of I/R injury and protection have not yet been fully elucidated. Circular RNA is a kind of ring-closed RNA, which is involved in the development of many human diseases. However, little is known about the circular RNAs involved in cardiovascular diseases, especially about their roles and mechanisms in, myocardial I/R injury and protection. Recently, we examined and analyzed the expression profiles of circular RNA in sham and I/R rat hearts, and found a differentially expressed circular RNA named circ3792.QPCR confirmed that circ3792 was upregulated in myocardial I/R. Preliminary studies showed that overexpression of circ3792 alleviated myocardial I/R injury, but its exact role needs to be further clarified, and its target and molecular mechanism underlying cardioprotection need to be elucidated. Therefore, this project aims at 1) further clarifying the cardioprotective effects of circ3792 in myocardial I/R; 2) identifying the direct target of circ3792 in cardioprotection; and 3) analyzing the way of circ3792 and its target in the cardioprotection. This study will reveal new function of circular RNA involved in myocardial I/R protection and provide new insight into the mechanism for how the circular RNA protects the heart from I/R injury. These knowledges might help to develop new therapeutic strategies for ischemic heart disease.

有效减轻缺血/再灌注（I/R）损伤是治疗缺血性心脏病的重要环节，但目前针对此的措施疗效有限。其中一个重要原因是I/R损伤和保护机制尚未阐明。环状RNA是一类环形闭合结构RNA，参与多种人类疾病的发生发展，但其在心血管疾病特别是心肌I/R损伤和保护中的作用与机制尚未明确。我们前期检测了大鼠正常和I/R心脏的环状RNA表达谱，筛选并验证I/R后差异表达的环状RNA—circ3792；初步研究发现过表达circ3792减轻心肌I/R损伤，但其确切作用有待进一步明确，其作用靶点和分子机制有待解析。因此，本项目旨在1）进一步明确circ3792在心肌I/R中的保护作用；2）确定circ3792心肌保护作用的直接靶点；3）解析circ3792及其靶点心肌保护的作用途径。本研究将发现参与心肌I/R保护的新环状RNA，揭示其减轻心肌I/R损伤的作用方式，为开发缺血性心脏病治疗的新策略提供实验证据。

有效减轻缺血/再灌注损伤，对降低心梗病人死亡率、提高其生活质量至关重要。但是缺血/再灌注损伤和保护机制尚未阐明。环状RNA是一类新型RNA分子，其在心血管疾病特别是心肌缺血/再灌注损伤和保护中的作用与机制尚不明确。我们基于前期工作，发现过表达circ3792能减轻心肌缺血/再灌注损伤,但其确切作用有待进一步明确。本项目主要研究发现：1）通过在体心肌缺血/再灌注模型和细胞氧糖剥夺/复灌模型，明确circ3792过表达在缺血/再灌注中的对心肌细胞和线粒体的保护作用；2）确定miR-24-3p是circ3792的直接作用靶点，并参与circ3792过表达的保护作用；3）解析了circ3792保护心肌抵抗I/R损伤的分子机制，即circ3792/miR-24-3p通过调控HO1水平维持线粒体稳态保护心肌细胞；4）筛选到一个心肌缺血/再灌注中新的功能性circRNA分子，circ4087。. 以上研究发现进一步明确了circ3792在心肌缺血/再灌注损伤的保护作用，揭示其通过miR24-3p调控HO1水平进而发挥保护作用的分子机制，为发展新的干预手段提供重要实验依据。