微小RNA-222在运动防治心脏老化所致心力衰竭中的作用及机制研究

Cardiac aging leads to heart failure while exercise training can prevent aging-induced heart failure. However, the molecular mechanism underlying the beneficial effects of exercise training in aging-induced heart failure is unclear. .With the grant support from National Natural Science Foundation of China (81200169), we found that miR-222 was responsible for exercise induced physiological hypertrophy and this finding had been accepted by Cell Metabolism. Our preliminary data also indicated that miR-222 was decreased by doxorubicin induced cardiomyocyte aging while overexpression of miR-222 could attenuate that. .Based on these findings, we will firstly identify the role of miR-222 in the beneficial effects of exercise training in aging-induced heart failure by both in vivo and in vitro loss-of-function and gain-of-function experiments. Normal aging and accelerated aging models will be used in vivo with transgenic mice and knockout mice. Normal aging and drug-induced aging models will be used in vitro with miR-222-overexpressing lentivirus and miR-222 RNA interference lentivirus. Secondly, based on the identified target genes including P27, Hmbox-1, HIPK1 and HIPK2, we will perform the rescue experiments in vitro and then in vivo to identify the downstream target of miR-222 that mediates its protective effects in aging-induced heart failure. .Our project will prove that miR-222 contributes to the protective role of exercise training in aging-induced heart failure and provide novel therapeutic targets for aging-induced heart failure.

运动可以保护心脏老化所致心力衰竭，但具体机制不清楚。我们发现微小RNA-222是介导运动诱导的生理性心肌肥大的关键微小RNA，结果发表于Cell Metabolism。进一步发现，增加微小RNA-222可防治心肌细胞老化，但它是否在运动防治心脏老化所致心力衰竭中起作用尚不清楚。本项目拟结合功能获得性（慢病毒表达载体、过表达小鼠）和功能缺失性实验（基因干扰慢病毒载体、敲除小鼠），在动物（自然老化和快速老化）和细胞水平（自然老化和药物诱导老化）明确微小RNA-222在运动防治心脏老化所致心力衰竭中的作用。然后基于已鉴定的靶基因P27、Hmbox-1、HIPK1和HIPK2，进行细胞和动物整体水平的挽救实验，揭示微小RNA-222介导运动防治心脏老化所致心力衰竭作用的分子基础。本项目将明确微小RNA-222在运动防治心脏老化所致心力衰竭中的作用及分子基础，为心脏老化所致心力衰竭的治疗提供新靶点。

我们先前发现微小RNA-222（miR-222）是介导运动诱导的生理性心肌肥大的关键微小RNA，结果发表于Cell Metabolism。运动可以保护心脏老化所致心力衰竭，但是参与运动诱导生理性心肌肥大的关键微小RNA——miR-222在心脏衰老及心力衰竭中的作用尚不清楚。在本项目中，我们首先基于miR-222敲除大鼠和野生型大鼠，发现miR-222敲除可以在D-半乳糖药物诱导的衰老模型中进一步降低心功能。同时，我们在自然衰老的大鼠中观察miR-222对心功能的影响，目前结果显示miR-222敲除暂未影响心功能（观察至90周龄）。接着，我们构建了成年鼠的心肌梗死（MI）模型，发现miR-222敲除加重成年鼠心肌梗死后的心肌损伤和心室重构，而miR-222过表达减轻心肌损伤和心室重构。进一步鉴定出miR-222的下游分子HIPK2敲除对D-半乳糖和血管紧张素II药物诱导的心肌损伤具有保护效应。最后，基于临床收集的MI患者入院时血清，发现MI患者入院时血清miR-222水平的降低对1年内不良预后具有预测能力。综上，本项目明确了miR-222和心脏衰老的关系，揭示了抑制miR-222加重心肌损伤而过表达miR-222减轻心肌损伤的作用，鉴定出miR-222的下游分子HIPK2敲除对心脏衰老和心肌损伤的保护效应，过表达miR-222或抑制HIPK2有望为防治心脏衰老和心肌损伤提供新的干预策略。