微小RNA-222与运动诱导的生理性心肌肥大的关系

Cardiac hypertrophy has been generally defined as either physiological or pathological. Pathological hypertrophy is often associated with increased risk of heart failure and sudden death while physiological hypertrophy is generally thought to be a benign adaptation. MicroRNAs (miRNAs, miRs) have emerged as key components of post-transcriptional gene regulators, participating in a wide range of biological processes. .Our preliminary data have indicated that miR-222 was elevated in both swimmming and voluntary wheel running-induced physiological hypertrophy while remained unchanged in pathological hypertrophy. Moreover, increased miR-222 promoted cardiomyocytes proliferation and was required for swimming-induced physiological hypertrophy. .Based on these finding, firstly, we will claify the role of miR-222 in physiological hypertrophy through in vivo loss-of-function (locked nucleic acid modified miR-222 inhibitor) and gain-of-function (Adeno-associated virus serotype-9, AAV-9) experiment. Secondly, combined gene array, bioinformatic analysis, luciferase reporter assay and Western Blot, the target genes of miR-222 will be identified. Finally, if elevated miR-222 is protective for heart failure will also be tested in vivo. .This study will identify a critical miRNA contributing to exercise-induced physiological hypertrophy and also provide a new therapeutic strategy to treat the failing heart.

心肌肥大包括生理性和病理性二种。病理性心肌肥大常导致心力衰竭和猝死，而生理性心肌肥大却对心血管疾病有保护效应。微小RNA是基因表达和调控的控制中心之一。我们的研究提示微小RNA-222在生理性心肌肥大显著升高（包括游泳诱导和跑步诱导的生理性心肌肥大），而在病理性心肌肥大却没有变化。微小RNA-222显著地促进了心肌细胞的增殖，抑制该微小RNA阻止了游泳诱导的生理性心肌肥大。本课题拟在此基础之上，结合微小RNA-222功能缺失性实验（微小RNA-222抑制剂）和功能获得性实验（腺病毒伴随病毒-9），明确其与生理性心肌肥大的关系。然后借助基因芯片、生物信息学分析、荧光素酶实验和免疫印迹法揭示微小RNA-222介导生理性心肌肥大的分子基础。最后探索增加微小RNA-222是否可以阻止心力衰竭的发生。本研究可能发现一个介导运动诱导的生理性心肌肥大发生的关键微小RNA，为心力衰竭的干预提供新的靶点。

心力衰竭严重危害人类健康，运动对于心力衰竭具有保护效应。运动可以导致生理性心肌肥厚，微小RNA广泛参与各种生理过程的调控，但是它在运动诱导的生理性心肌肥大中的作用尚不清楚。在本项目中，我们采用微小RNA芯片筛选结合荧光定量PCR验证的方式，发现微小RNA-222在游泳和跑步二种不同的运动方式诱导的生理性心肌肥大中均显著升高，且它的升高特异性地发生于心肌细胞。细胞水平的研究发现，增加微小RNA-222可以促进心肌细胞的肥大和增殖，而降低微小RNA-222可以减小心肌细胞的体积和增殖。此外，增加微小RNA-222可以抵抗阿霉素和去血清培养诱导的心肌细胞的凋亡。动物水平的研究发现，微小RNA-222的升高是运动诱导的生理性心肌肥大所必须。构建的可诱导心脏特异性的微小RNA-222过表达小鼠对于心脏缺血再灌注损伤所致的心室重构具有保护效应，包括改善心功能、减轻心肌纤维化、降低凋亡以及促进新的心肌细胞的形成等多个方面。除了经典的微小RNA-222的靶基因P27之外，我们还鉴定出了三个新的微小RNA-222的靶基因即Hmbox1、HIPK1和HIPK2。总之，本项目鉴定出了一个运动诱导的生理性心肌肥大的关键微小RNA，并初步揭示了这个微小RNA（微小RNA-222）在防治缺血再灌注损伤所致心室重构不良中的作用。