Ameliorative effects of trimetazidine on bone marrow mesenchymal stem cells viability through Bcl-2 expression

AIM: To investigate whether Trimetazidine(TMZ) can improve the survival of Bone marrow mesenchymal stem cells(MSCs) in an ex-vitro model of hypoxia,as well as survival,differentiation,and subsequent activities of transplanted MSCs in rat hearts with acute myocardial infarction(AMI),and discuss the mechanism. METHODS: MSCs at passage 3 were examined for their viability and apoptosis by transmission electron microscope,and flow cytometry following cultured in serum-free medium and exposed to hypoxia(5%CO2,95%N2) for 12 h with or without TMZ.Thirty wistar rats were divided into 3 groups(n=10 in every group),including group I(AMI control),group II(MSCs transplantation alone),and group III(TMZ+MSCs).Rat MSCs(4×107cells) were injected into peri-infarct myocardium(MSCs and TMZ+MSCs groups) thirty minutes after coronary artery ligation.The rats in TMZ+MSCs group were additionally fed TMZ with 2.08 mg·kg-1·d-1 from 3 days before AMI to 28 days after AMI.Cardiac structure and function was assessed by echocardiography 28 days after transplantation.The survival and differentiation of transplanted cells were detected by immunofluorescent staining.The cellular apoptosis in the peri-infarct region was detected with TUNEL assay.Furthermore,apoptosis-related proteins(Bcl-2,Bax) within the post-infarcted myocardium were detected with Western blotting.RESULTS:In hypoxic culture,the TMZ-treated MSCs displayed a two-fold decrease in apoptosis under serum-free medium and hypoxia environment.In vivo,cardiac infarct size was significantly smaller,cardiac function significantly improved in the MSCs and TMZ+MSCs groups than those in the control group.Combined treatment with TMZ and MSCs implantation demonstrated a further decrease in MSCs apoptosis,a further increase in MSCs viability,a further decrease in infarct size,and a further improvement in cardiac function as compared with MSCs alone.Western blotting indicated that the expression of anti-apoptotic protein Bcl-2 was upregulated,while the pro-apoptotic protein Bax was downregulated in the TMZ+MSCs group,compared with that in the MSCs group.CONCLUSION: Implantation of MSCs combined with TMZ treatment is superior to MSCs monotherapy for MSCs viability and cardiac function recovery.The up-regulating of Bcl-2 maybe the potential mechanism.