肺动脉高压中miR-125a-5p-增强子-FPR1/2通路调控右心肥厚的机制研究

右心衰竭是肺动脉高压（PAH）患者最主要的死亡原因，而右心肥厚是右心衰竭重要的病理生理过程。我们前期研究发现miR-125a-5p在改善肺血管重塑以外，还可单独改善PAH鼠的右心肥厚，且肥厚心肌中miR-125a-5p表达下调。我们发现成熟miR-125a-5p尚存于细胞核内，且其存在与增强子的结合位点，并能正向调控靶基因FPR1/2。FPR1/2具有减弱炎症、保护心肌等作用。因此我们提出，miR-125a-5p表达缺陷调控FPR1/2表达下降，使其抗炎作用减弱，促进心肌肥厚的发生，最终导致右心衰竭。本项目拟通过野百合碱诱导和肺动脉结扎法构建右心肥厚模型，并应用基因敲除鼠首次在体内和体外验证核内miR-125a-5p-增强子-FPR1/2的正向调控机制在右心肥厚发生发展中的作用。预期结果有助于深入理解右心肥厚的发生机制，为临床上防治右心衰竭开拓新靶点。

Right heart failure is the main cause of death in pulmonary arterial hypertension (PAH) patients, and right ventricular hypertrophy is an important pathophysiological process of right heart failure. Our previous studies found that miR-125a-5p could not only improve pulmonary vascular remodeling,but also independently improve right ventricular hypertrophy in PAH rats, and confirmed that the expression of miR-125a-5p was down-regulated in the process of right ventricular hypertrophy. Then，we found that mature miR-125a-5p is still present in the nucleus, and it has an enhancer binding site and can positively regulate the target gene FPR1/2.Moreover, FPR1/2 can attenuate inflammation and protect myocardium. Therefore, we propose that the defective expression of miR-125a-5p regulates the decline of FPR1/2 expression, weakens its anti-inflammatory effect, promotes the occurrence of myocardial hypertrophy, and ultimately leads to right heart failure. In this project, we intend to construct right heart hypertrophy models by monocrotaline induction and pulmonary artery banding, and use knockout mice for the first time in vivo and in vitro to verify the positive regulation mechanism of miR-125a-5p-enhancer-FPR1/2 on the role of development of right heart hypertrophy. The expected results will help to understand the mechanism of right heart hypertrophy and open up a new target for prevention and treatment of right heart failure in clinical.