二氯乙酸钠改善糖尿病小鼠内皮祖细胞功能及其在脑缺血损伤治疗中的应用

The treatment of diabetic cerebrovascular complication is still a global problem to date, and it is necessary to investigate new therapeautic strategies for cerebrovascular complication of diabetes. Endothelial progenitor cells (EPC) participate in angiogenesis that correlates inversely with the severity of cerebral ischemic injury in diabetes. EPCs were both reduced and dysfunctional in diabetic mice. Our previous studies demonstrated that sodium dichloroacetate (DCA) could increase EPC number and improve EPC function. Accordingly,we hypothesize that DCA reduces diabetic cerebral ischemic injury via increasing EPC number and improving EPC function. To test this hypothesis, this project will perform following 4 aims: 1) to determine the relationship between the reduced diabetic cerebral ischemic injury produced by DCA and the increase of EPC number and the improvement of EPC function; 2)to test that DCA enhances the effects of diabetic EPC transplantation on cerebral ischemic injury in mice. 3) to investigate the mechanisms underlying the EPC number increase produced by DCA; 4) to investigate the mechanisms underlying the EPC function improvement produced by DCA. Clinical trials show that a higher EPC number is related with a better prognosis in cardio-cerebrovascular patients, and EPCs may serve as a therapeutic target of cardio-cerebrovascular diseases. Therefore, this project may provide a new therapeutic strategy for diabetic vascular complication.

糖尿病脑血管并发症的防治目前依然是个世界性难题，探索新治疗方法有现实的意义。糖尿病脑缺血损伤的严重程度与血管新生有关，而血管新生与内皮祖细胞(EPC)的数量和功能密切相关。糖尿病小鼠EPC的数量和功能均出现异常，而我们前期工作表明二氯乙酸钠(DCA)可改善糖尿病EPC的数量和功能。基于此，我们推测：DCA可通过改善糖尿病小鼠EPC的数量和功能，从而减轻其脑缺血损伤。本项目拟通过下列实验来验证该假设：确定DCA减轻糖尿病小鼠脑缺血损伤与其改善EPC数量和功能的关系;研究DCA增强糖尿病EPC对脑缺血损伤的治疗作用;阐明DCA增加糖尿病小鼠外周血中EPC数量的机制;阐明DCA改善糖尿病EPC功能的机制。临床研究证实，外周血中EPC数量高的心脑血管疾病患者预后比较好，EPC可作为治疗心脑血管疾病的新靶点，所以本项目的研究有可能为糖尿病血管并发症的治疗和预防提供新的思路和途径。

糖尿病脑血管并发症的防治目前依然是个世界性难题，探索新治疗方法有现实的意义。糖尿病脑缺血损伤的严重程度与血管新生有关，而血管新生与内皮祖细胞(EPC)的数量和功能密切相关。我们的研究证实，1）与对照小鼠比较，糖尿病小鼠的EPC的数量和功能均降低、脑缺血损伤明显加重、脑缺血区血管新生能力显著降低，二氯乙酸钠（DCA）灌胃给药可显著改善上述变化。提示，DCA减轻糖尿病小鼠脑缺血损伤可能与其改善EPC数量和功能有关。2）DCA体外孵育在增加糖尿病EPC功能的同时，可显著增强糖尿病EPC对脑缺血损伤、脑缺血区血管新生的改善作用。提示，DCA可增强糖尿病EPC对脑缺血损伤的治疗作用。3）DCA增加糖尿病小鼠外周血中EPC数量可能部分与其降低EPC凋亡数量、增强EPC动员能力有关；而凋亡数量增加可能部分与其氧化应激水平升高有关，EPC动员能力增强可能部分与其胞内NO水平升高有关。4）DCA改善糖尿病小鼠EPC功能可能与其降低EPC中O2-水平和增高EPC中NO水平有关，DCA的这个作用可能与其提高EPC中的p-eNOS、eNOS和MnSOD蛋白表达水平有关。综上所述，DCA可改善糖尿病小鼠受损的EPC数量和功能，从而减轻小鼠的脑缺血损伤。同时，通过DCA体外干预改善受损的EPC功能，可增强其对糖尿病小鼠脑缺血损伤的治疗作用。临床研究证实，外周血中EPC数量高的心脑血管疾病患者预后比较好，EPC可作为治疗心脑血管疾病的新靶点，所以本项目的研究有可能为糖尿病血管并发症的治疗和预防提供新的思路和途径。