miR-203在EPO改善缺血损伤心肌预后中的调控作用及其机制

Erythropoietin (EPO) has recently been shown cardioprotective effect in animal models of myocardial infarction. In our study in 2012, we have described that the cardioprotective effects of EPO was at least partially mediated by upregulated SDF-1 expression via activation of the JAK2/STAT3, which resulted in augmented neovascularization and antiapoptotic effect. In our preliminary experiments, we found that EPO up-regulated the expression of miR-203 in hypoxia-induced cardiomyocytes,and inhibition of miR-203 decreased the expression of SDF-1 and increased the munber of apoptotic cells. But the exact mechanisms are still not very clear. We plan to investigate if the overexpression or slience of miR-203 have an effect on the production of SDF-1 and EPO cardioprotection in myocardial infarction model. Moreover, we should study if miR-203 regulate STAT3 signaling pathway by its downstream target gene ,suppressor of cytokine signaling 3 (SOCS-3),to affect the expression of SDF-1. This study will try to demonstrate that the role of miR-203 in SDF-1- mediated the cardioprotection of EPO, which should supply some new therapeutic strategies and treatment targets in myocardial ischemic injury.

促红细胞生成素（EPO）已被证实对缺血心肌有明显的保护作用，我们研究发现(2012)，EPO通过活化STAT3信号通路促进了SDF-1的表达，从而抑制细胞的凋亡、促进血管新生等，进而发挥其保护作用。前期芯片筛选和定量PCR验证发现： EPO能促进缺氧心肌细胞miR-203的表达，且抑制miR-203能下调SDF-1的表达并增加凋亡细胞数量,但miR-203是否介导了EPO对缺血损伤心肌组织的保护及其具体的机制并不十分清楚。本课题将建立小鼠缺血性心肌梗死模型，采用慢病毒过表达和反义核苷酸等技术，研究miR-203在SDF-1的表达和EPO心肌保护过程中的作用。并探讨其是否通过作用于下游靶基因细胞因子信号传导抑制因子3（SOCS-3）来调控STAT3信号通路，从而影响SDF-1的表达，进一步明确EPO的作用机制，为其临床应用提供新的思路和治疗靶点。

促红细胞生成素(EPO)已被证实对缺血心肌有明显的保护作用,我们前期研究发现，EPO通过活化STAT3信号通路促进了SDF-1的表达,从而抑制细胞的凋亡、促进血管新生等,进而发挥其保护作用。通过本课题我们进一步发现，EPO能促进缺氧心肌细胞表达microRNA-203，进而抑制其靶蛋白细胞信号传导抑制因子（SOCS3）的表达。而SOCS3是JAK2/STAT3通路活化的抑制分子，EPO抑制其表达后，能促进信号传导与转录激活因子3（STAT3）的磷酸化进而激活JAK2/STAT3通路，促进下游蛋白分子如基质细胞衍生因子1（SDF1）的表达及分泌，从而对缺氧损伤的心肌细胞起到保护作用。本实验证实了EPO通过上调microRNA-203的表达，激活JAK2/STAT3通路并刺激SDF-1的分泌，达到对受损心肌的保护作用。进一步阐明了EPO保护缺血损伤心肌的具体作用机制。