Transplantation of mesenchymal stem cells preconditioned with diazoxide, a mitochondrial ATP-sensitive potassium channel opener, promotes repair of myocardial infarction in rats.
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.
Department of Anatomy and Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai, P.R. China.
Xiaojun
X
Cui
Haijie
H
Wang
Haidong
H
Guo
Cun
C
Wang
Hong
H
Ao
Xiaoqin
X
Liu
Yu-zhen
YZ
Tan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D024510:Muscle Development / Q000502:physiology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020107:Troponin T / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D016277:Ventricular Function, Left / Q000502:physiology
D003652:Decanoic Acids; D006880:Hydroxy Acids; D015221:Potassium Channels; D020107:Troponin T; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D016222:Fibroblast Growth Factor 2; C052853:5-hydroxydecanoic acid; D017228:Hepatocyte Growth Factor; D003094:Collagen; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D003981:Diazoxide