microRNA-27a调控ADCY-6通路促进心肌肥厚的机制研究

Hypertrophic cardiomyopathy leads to heart failure and sudden death, but mechanism is unclear. MicroRNA plays an important role in cardiovascular diseases. Mir-27a was found to be activated in the samples of hypertrophic cardiomyopathy in our previous work. We also observed that overexpression of Mir-27a aggravated transverse aortic constriction(TAC)-induced experimental cardiac hypertrophy. Mir-27a may inhibit the expression of ADCY-6 and remarkably increase the severity of myocardial hypertrophy and myocardial fibrosis. However, the underlying mechanism is remained unclear. The goal of this study is to determine how Mir-27a cause cardiac hypertrophy by using Mir-27a transgenic and knock out mice. Specifically, the aims are: 1) to determine how Mir-27a is regulated, 2) to elucidate the molecular mechanisms of Mir-27a in myocardial hypertrophy and myocardial fibrosis; 3) to identify the clinical relationship between Mir-27a and manifestations. Our research will shed light on how Mir-27a participates the pathogenesis of cardiac hypertrophy, and provide the theoretical and experimental basis for intervention of hypertrophy cardiomyopathy.

肥厚性心肌病可以导致心衰和猝死，其机制尚不完全清楚。microRNA在心血管疾病发病过程中发挥重要作用。我们前期预实验发现肥厚性心肌病患者血清和心肌标本miR-27a表达升高；小鼠注射miR-27a激动剂加剧心肌肥厚和心肌纤维化；并可以抑制腺苷酸环化酶6(ADCY-6)的表达，推测miR-27a可能通过抑制ADCY-6表达促进心肌肥厚。但miR-27a水平是如何升高、其导致心肌细胞肥厚和心肌纤维化的机制尚不清楚。本课题在基因敲除动物模型及体外细胞培养基础上，通过研究：1）miR-27a如何在病理情况下升高；2）阐明miR-27a在肥厚性心肌病中促进心肌肥厚和心肌纤维化的作用和分子机制；3）明确miR-27a与肥厚性心肌病的临床表现及病情评估的相关性来阐明miR-27a在肥厚性心肌病中的关键作用，为肥厚性心肌病的防治策略和病情评估提供重要的理论依据和实验基础。

肥厚型心肌病存在较高的发病率、部分患者预后不良、现有治疗手段局限、发展机制尚未完全明确，发展过程可能受非编码RNA的调控，其中microRNA-27a在肥厚型心肌病患者中存在着差异性表达。通过体外、体内实验探究microRNA-27a调控其靶基因ADCY-6在心肌细胞肥大及心肌肥厚模型重构过程的作用。在主动脉弓缩窄模型和异丙肾上腺素心肌细胞肥大模型中发现，microRNA-27a调控靶基因、抑制ADCY-6表达引起心肌重塑、肥厚的发展。进一步在动物及细胞研究中发现抑制microRNA-27a表达可以延缓重构和肥厚的发生。上述研究有望为肥厚性心肌病诊疗、延缓心肌肥厚的发展提供实验理论依据。