RNA编辑酶ADAR2介导运动诱导的生理性心肌肥厚及其机制研究

Exercise training is an effective non-drug treatment for heart failure. Investigation of molecular mechanism underlying physiological cardiac hypertrophy induced by exercise will help to develop drugs to heart failure. ADAR2 is associated with the proliferation of multiple cells, but the role of ADAR2 in physiological cardiac hypertrophy is unclear. Our previous data showed that ADAR2 was upregulated in heart samples of swimming mice, and ADAR2 overexpression promoted proliferation and inhibited apoptosis in neonatal rat cardiomyocytes, while suppression of ADAR2 led to the opposite results, indicating that ADAR2 might regulate physiological cardiac hypertrophy. miR-34a was identified as a potential downstream molecule of ADAR2. In this project, we will firstly clarify the relationship between ADAR2 and physiological cardiac hypertrophy based on the gain of function and loss of function experiments in vitro and in vivo. Secondly, the molecular mechanism of ADAR2 in physiological cardiac hypertrophy will be elucidated by defining the editing effect of ADAR2 on miR-34a at the molecular level and performing the functional rescue experiments in cellular and mice level. Finally, we will further explore the potential effect of ADAR2 in preventing cardiac remodeling and heart failure following myocardial ischemia-reperfusion injury. After this project, we will clarify the role of ADAR2 in physiological hypertrophy, and provide a new therapeutic target for heart failure.

运动训练是心力衰竭的一种有效的非药物治疗方法，探索运动诱导的生理性心肌肥厚的分子机制有助于开发防治心力衰竭的药物。ADAR2与多种细胞的增殖相关，但与生理性心肌肥厚的关系尚不清楚。我们的预实验发现，ADAR2在生理性心肌肥厚时上调。过表达ADAR2可以促进心肌细胞增殖，抑制其凋亡，而抑制ADAR2效果相反，提示ADAR2可能与生理性心肌肥厚相关。我们也初步发现ADAR2的一个潜在下游：miR-34a。本项目首先基于细胞和动物水平的功能获得性与缺失性实验，明确ADAR2与生理性心肌肥厚的关系。然后，进行ADAR2对miR-34a的编辑作用探索和功能逆转实验，明确ADAR2介导生理性心肌肥厚的分子机制。最后，探索增加ADAR2是否可以防治心肌缺血再灌注损伤所致的心室重构和心力衰竭。通过本项目，我们将明确ADAR2调控生理性心肌肥厚的分子机制，发掘出一个治疗心力衰竭的新靶点。

运动训练是心力衰竭的一种有效的非药物治疗方法，探索运动诱导的生理性心肌肥厚的分子机制有助于开发防治心力衰竭的药物。关于心脏的转录后调控，特别是RNA编辑方面的研究仍然很少。ADAR2是一种将双链RNA中的腺苷编辑为肌苷的酶，而RNA编辑与诸多人类疾病有关。但是ADAR2与生理性心肌肥厚和心脏保护的关系尚不清楚。我们发现，在运动训练后的生理性心肌肥厚心脏中的ADAR2表达上调。AAV9介导的心脏特异性ADAR2过表达可减轻急性心肌梗死、心肌梗死的心脏重构和阿霉素诱导的心脏毒性。在体外，过表达ADAR2不仅可以抑制阿霉素诱导的心肌细胞的凋亡，还能促进新生大鼠心肌细胞的增殖。在机制上，ADAR2可以通过RNA编辑的方式调控心肌细胞中成熟miR-34a的表达，可能通过对miR-34a或其靶基因（Sirt1、Cyclin D1和Bcl2）的调控影响心肌细胞的促增殖和抗凋亡作用。这些结果表明，运动诱导的ADAR2保护心脏免受心肌梗死损伤和阿霉素诱导的心脏毒性。因此，ADAR2过表达或通过ADAR2进行转录后的RNA编辑可能是一种有前景的心脏病治疗策略。