MEF2A/miR-92a/GDF11信号轴调控冠状动脉慢血流血管内皮功能及左心室功能的作用机制

Reduced left ventricular function was confirmed in coronary slow flow (CSF), although there is no effective treatment for this complex disorder currently. It was claimed that impaired vascular endothelial function induced CSF, however, the underlying mechanisms remain unclear. Serum microRNA microarray analysis identified that miR-92a increased and correlated with vascular endothelial function and left ventricular function in patients with CSF according to our previous research. Moreover, high expression of MEF2A and miR-92a in addition to low expression of GDF11 were revealed in coronary arteries of porcine CSF model. Software predicted that miR-92a could bind to transcription factor MEF2A and downregulate the expression of GDF 11. Therefore, we hypothesized that increased expression of MEF2A in SCF vascular endothelial cells upregulates miR-92a expression, which negatively regulates GDF11, thereby regulating vascular endothelial function and left ventricular function. Combined in vitro and in vivo approach, our study aims to clarify the relationship between serum miR-92a expression and endothelial function as well as left ventricular function in CSF patients, and investigate the mechanisms of MEF2A promoting miR-92a transcription and miR-92a negatively regulating GDF11 expression. Finally, porcine CSF model was established to determine the mechanisms of MEF2A/miR-92a/GDF11 axis regulating vascular endothelial function and left ventricular function. Our findings will provide new targets and directions for the treatment of CSF.

冠状动脉慢血流（CSF）导致左心室功能减低，尚无有效治疗方法。血管内皮功能减低是主要发病原因之一，但机制不清。前期基因芯片筛选CSF患者血清miR-92a表达升高，且其与血管内皮功能及左心室功能相关；在CSF猪冠状动脉组织发现MEF2A和miR-92a高表达，GDF11低表达。软件预测miR-92a可与转录因子MEF2A结合，并下调GDF11表达。建立假说：CSF血管内皮细胞MEF2A表达增高，上调miR-92a，miR-92a负性调控GDF11，从而调控血管内皮功能及左心室功能。本研究结合体内外实验，明确CSF患者血清miR-92a表达与血管内皮功能和左心室功能的关系；研究MEF2A促进miR-92a转录，及miR-92a负性调控GDF11的机制；最后建立CSF猪模型，明确MEF2A/miR-92a/GDF11轴调控CSF血管内皮功能及左心室功能的机制。研究结果将为CSF治疗提供新靶点。

冠状动脉慢血流（CSF）导致左心室功能减低，可导致恶性心血管事件，受到临床密切关注。但目前发病机制不明确，尚无有效治疗方法。研究认为血管内皮功能减低是主要发病原因之一，但机制不清。本项目根据前期研究结果，建立假说：CSF血管内皮细胞MEF2A表达增高，上调miR-92a，miR-92a负性调控GDF11，从而调控血管内皮功能及左心室功能。.本研究结合体内外实验，开展以下研究：以中国医科大学附属第一医院患者为基础开展病例-对照研究，检测180例CSF患者及194例对照者血清中miR-92a表达，明确CSF患者血清中miR-92a表达与血管内皮功能和左心室功能相关性；构建MEF2A及miR-92a过表达与表达沉默的CSF-HAEC模型，明确MEF2A促进miR-92a转录调节CSF血管内皮功能的机制；同时构建miR-92a及GDF11过表达与表达沉默的CSF-HAEC模型，并应用双荧光素酶报告基因实验明确miR-92a负性调控GDF11影响CSF血管内皮功能的机制以及GDF11通过调控AMPK/eNOS通路影响血管内皮功能的机制；最后在CSF猪模型中验证MEF2A、miR-92a和GDF11等分子表达情况，明确MEF2A/miR-92a/GDF11信号轴调控血管内皮功能及左心室功能机制。.本项目将超声心动图新技术和分子生物学技术相结合，从宏观到微观，从体内、体外实验，不同水平不同层面进行研究，研究结果为阐明CSF的发病机制提供新思路，为CSF的诊断和治疗提供新的靶点和方向，具有重要的临床意义。本项目已发表论文18篇，其中SCI收录13篇。