miR-21抑制PTEN介导心脏衰老

Aging is among predominant risk factors for cardiovascular diseases. MicroRNAs (miRNAs, miRs) participate in many physiological and pathological processes in the cardiovascular system. However, the role of miRNAs in cardiac aging has not been completely understood. Our preliminary data showed that miR-21 was upregulated in multiple types of cardiac aging models both in vivo and in vitro. Overexpression of miR-21 could induce aging of the neonatal rat cardiomyocytes. In this project, we will further investigate the role of miR-21 in cardiac aging by gain-of-function and loss-of-function experiments both in vitro and in vivo. Based on the target gene PTEN that we have identified, rescue experiments will be performed to fully prove the role of PTEN in miR-21 mediated cardiac aging. This project will provide a novel therapy for cardiac aging.

心脏衰老是引起多种心脏疾病的主要原因，微小RNA广泛参与心血管疾病的各种病理生理过程，但它在心脏衰老中的作用尚未完全明确。我们的前期研究发现，微小RNA-21在细胞水平和动物水平的多种心脏衰老模型中均显著升高，过表达微小RNA-21可以诱导新生大鼠心肌细胞衰老。在本次申请课题中，我们拟基于已建立的细胞和动物心脏衰老模型，通过功能获得性和缺失性实验，明确微小RNA-21与心脏衰老的关系。此外，基于前期已鉴定出的靶基因PTEN，我们将通过细胞水平的功能挽救实验，明确微小RNA-21介导心脏衰老的分子基础，为心脏衰老的防治提供新的方法。

心脏衰老是诱发心脏疾病的独立危险因素。心脏衰老所致的心力衰竭仍缺乏有效的干预措施。探索心脏衰老的分子机制，将有助于挖掘出治疗心脏衰老的新方法。我们综合运用微小RNA芯片和荧光定量PCR，发现miR-21在自然衰老小鼠心脏、D-半乳糖（D-gal）药物诱导衰老小鼠心脏、阿霉素（Dox）体外诱导心肌细胞衰老这3个模型中均显著上调。在Dox诱导心肌细胞衰老的模型中，过表达miR-21可以促进心肌细胞衰老，而抑制miR-21具有相反的作用。通过功能挽救实验，证实PTEN是miR-21的靶基因，PTEN下调介导了miR-21促进心肌细胞衰老的作用。进一步基于miR-21敲除小鼠，发现miR-21敲除可以减轻D-gal药物诱导的心脏衰老，改善心功能。综上，我们的研究明确了miR-21和心脏衰老的关系，揭示了miR-21通过靶基因PTEN促进心脏衰老的分子基础，miR-21可能成为治疗心脏衰老的干预靶点。