Department of Anatomy and Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai, P.R. China.
Tohoku J Exp Med. 2010 Feb;220(2):139-47. doi: 10.1620/tjem.220.139.
Myocardial infarction (MI) causes myocardium injury and scar formation, and the transmural infarction is associated with ventricular hypofunction. Stem cell transplantation therapy has improved cardiac function in animal models of MI. However, the poor survival of the donor cells in the host myocardium hampers the therapeutic efficacy of stem cell transplantation. Diazoxide, a mitochondrial ATP-sensitive potassium channel opener, has been applied to suppress cell apoptosis and promote cell survival. We therefore assessed the effects of diazoxide on the selected mesenchymal stem cells (SMSCs). Pretreatment of SMSCs with diazoxide (200 micromol/L) for 30 min protected cells from oxidative stress injury by upregulating the expression of basic fibroblast growth factor and hepatocyte growth factor mRNAs and phospho-Akt and by preventing mitochondral cytochrome c translocation into the cytoplasm. Expression of mRNAs and proteins was detected by RT-PCR and western blot analyses. Thirty min after establishment of MI (the ligation of the left anterior descending of coronary artery) in female rats, the male rat SMSCs preconditioned with diazoxide were injected at four sites on the edge of the infarcted area. At 4 weeks after cell tranplantation, the donor cells in the recipient myocardium were tracked with Y chromosome. Preconditioning with diazoxide improved the survival rate of the transplanted SMSCs, compared to the untreated SMSCs. Moreover, transplantation of the diazoxide-pretreated SMSCs reduced the infarct size and increased left ventricular function, as judged by transthoracic echocardiography. In conclusion, diazoxide preconditioning is effective to promote SMSCs survival under oxidative stress and attenuates cardiac injury in MI.
心肌梗死（MI）导致心肌损伤和瘢痕形成，透壁性梗死与心室功能低下有关。干细胞移植治疗已改善了 MI 动物模型的心脏功能。然而，供体细胞在宿主心肌中的存活率低，阻碍了干细胞移植的治疗效果。二氮嗪是一种线粒体 ATP 敏感性钾通道开放剂，已被应用于抑制细胞凋亡和促进细胞存活。因此，我们评估了二氮嗪对选定的间充质干细胞（SMSCs）的影响。用二氮嗪（200μmol/L）预处理 SMSCs30min 可通过上调碱性成纤维细胞生长因子和肝细胞生长因子 mRNA 和磷酸化 Akt 的表达，防止线粒体细胞色素 c 向细胞质易位，从而保护细胞免受氧化应激损伤。通过 RT-PCR 和 Western blot 分析检测 mRNA 和蛋白质的表达。在雌性大鼠 MI（左前降支冠状动脉结扎）建立 30min 后，将用二氮嗪预处理的雄性大鼠 SMSCs 注射到梗死区边缘的四个部位。细胞移植后 4 周，用 Y 染色体追踪受体内的供体细胞。与未经处理的 SMSCs 相比，用二氮嗪预处理可提高移植 SMSCs 的存活率。此外，移植用二氮嗪预处理的 SMSCs 可减少梗死面积并通过经胸超声心动图增加左心室功能。总之，二氮嗪预处理可有效促进 SMSCs 在氧化应激下的存活，并减轻 MI 中的心脏损伤。
