MicroRNA在反复肢体缺血后适应改善心肌梗死后心室重构中的功能及调控机制研究

Cardiac remodeling after acute myocardial infarction increases gradually, which could result in heart failure and cardiovascular death. However, there is lack of effective strategies to prevent the progress. Accumulated evidences showed that repeated limb ischemic postconditioning (RIPC) could protect the heart against remodeling induced by myocardial infarction, yet the mechanisms remained elusive. In our previous studies, RIPC was given to mice with myocardial infarction for 28 days, then the mice were killed and microRNA sequencing was performed using cardiac tissues. The results suggested that RIPC mediate microRNA levels and protect against cardiac remodeling. We then selected 8 candidate microRNAs to further the studies in this program using genetic engineering or key target intervention techniques. We will investigate the role of candidate microRNAs in cardiac remodeling after myocardial infarction and the regulated mechanisms by RIPC in vivo and in vitro experiments. Furthermore, we will screen and assess which candidate microRNAs could work as biomarkers in animal and clinical studies. Our research will contribute to reveal the novel mechanisms of RIPC in cardiac remodeling after myocardial infarction and provide evidence for the clinical use of candidate microRNAs.

急性心肌梗死后心室重构的发病率逐年上升，导致心力衰竭、心源性死亡等不良临床事件，但有效遏制手段极其匮乏。反复缺血后适应（RIPC）对心肌梗死后心室重构具有确切的保护作用，但作用机制仍不清楚。项目组对心肌梗死小鼠实施28天RIPC，心脏组织microRNA测序发现心肌梗死后microRNA的变化程度与RIPC密切相关，提示RIPC通过调控microRNA改善心肌梗死后心室重构，并筛选、验证8种microRNA为候选microRNA继续深入研究。本项目拟从细胞、动物、人群三个层面设计系列实验，采用基因工程或干预关键靶点等技术，揭示候选microRNA在心肌梗死后心室重构中的作用及RIPC的调控机制，筛选并评价候选microRNA作为预后预测和疗效评价生物标志物的价值。研究成果将为深入认识RIPC对心肌梗死后心室重构的作用机制以及microRNA的临床应用转化提供依据。

急性心肌梗死后心室重构的发病率逐年上升，导致心力衰竭、心源性死亡等不良临床事件，但有效遏制手段极其匮乏。反复缺血后适应（RIPC）对心肌梗死后心室重构具有确切的保护作用，但作用机制仍不清楚。项目组设计了细胞、动物、人群三个层面的系列实验，采用基因工程或干预关键靶点等技术，揭示了miR-20b-5p、miR-182-5p在心肌梗死后心室重构中表达上调，具有导致心肌梗死后心室重构的作用；PIPC可下调miR-20b-5p、miR-182-5p表达，改善心肌梗死后心室重构。研究成果为深入认识 RIPC 对心肌梗死后心室重构的作用机制提供新证据。另外，本项目发现的microRNAs有望具有转化前景，为临床治疗心肌梗死后心室重构、心力衰竭等不良预后提供新型治疗技术。