miR-22靶向调控CBP基因对缺血再灌注心肌的多重保护作用及机制研究

Myocardial ischemia reperfusion injury (IRI) is an important factor in reducing the clinical effects of reperfusion therapy for coronary heart disease. However, a variety of preventive measures at present have a limited cardioprotective effect, which may be ascribed to the unitary role of intervention targets. CREB binding protein (CBP) as a common regulator of numerous signal transduction pathways, is involved in the regulation of myocardial IRI. Previous work from our laboratory has demonstrated that CBP gene silencing could potently attenuate myocardial IRI through its anti-inflammation and anti-apoptosis effects. The latest study has shown that there are dozens of miRNAs differentially expressed in the ischemia reperfusion myocardium. Among such miRNAs, miR-22 was found to be highly down-regulated. Furthermore, the software TargetScan predicts that the 3'-UTR of CBP mRNA contains critical target sites for miR-22, suggesting miR-22 may confer cardioprotection via the targeted regulation of CBP. Nevertheless, the exact regulatory mechanism is still not elucidated so far. In the present study, we attempt to use the idea of "phenomenon description-overall effect-molecular mechanism", to observe the influence of miR-22 overexpression or silencing on myocardial IRI and explore the multiple protective effect and molecular mechanism of miR-22 targeted CBP gene regulation. The successful application of our research program will provide a novel therapeutic strategy for the prevention of myocardial IRI.

心肌缺血再灌注损伤(IRI)是影响冠心病再灌注治疗效果的重要因素，然而目前各种防治措施对心肌的保护作用有限，其原因与干预靶点的作用单一性有关。CREB结合蛋白(CBP)作为众多信号转导途径的共同调节子，可参与多基因改变介导的心肌IRI。本课题组前期研究发现，CBP基因沉默可通过抗炎、抗细胞凋亡对再灌注心肌发挥保护作用。最新研究表明，再灌注心肌中有数十种表达差异的miRNA，其中miR-22表达明显下调。生物信息学方法预测miR-22与CBP mRNA3'-UTR存在关键结合位点，提示miR-22可靶向调控CBP基因发挥心肌保护。但作用方式与调控机制如何？均未见报道。本项目拟以"现象描述-整体作用-分子机制"的思路为指导，观察过表达和沉默miR-22对心肌IRI的影响，并深入探讨miR-22靶向调控CBP基因对再灌注心肌的多重保护作用及信号分子机制，为开辟新的心肌IRI防治途径奠定理论基础。

心肌缺血再灌注损伤(IRI)是影响缺血心肌再灌注治疗效果的重要因素，然而目前各种防治措施对再灌注心肌的保护作用有限，其原因可能与干预靶点的作用单一性有关。CREB结合蛋白(CBP)作为众多信号转导途径的共同调节子，参与多基因表达改变介导的心肌IRI。本项目以“现象描述-整体作用-分子机制”的思路为指导，观察了过表达miR-22对心肌IRI的影响。研究结果发现心肌再灌注时，不管是细胞水平还是动物水平，miR-22均可通过下调其靶基因CBP的表达，调节CBP相关信号通路的活性，对心肌细胞发挥抗炎、抗凋亡的作用，产生多重保护效应。总之，本项目的实施为心肌缺血再灌注损伤的有效防治提供了新的干预靶点及理论依据。