[Erythropoietin enhances the therapy potency of autologous bone marrow stromal cells in a rat heart infarction model via phosphatidylinositol-3-kinase/Akt pathway].
OBJECTIVE
Erythropoietin (EPO) induces angiogenesis and inhibits apoptosis through the phosphatidylinositol-3-kinase/Akt (PI3-K/Akt) pathway. Transplantation of mesenchymal stromal cells (MSC) has been shown to improve heart perfusion and function post myocardial ischemia. We investigated whether EPO enhances the therapeutic potency of MSC transplantation in rats with experimental myocardial infarction (MI).


METHODS
Wistar rats were divided into four groups (n=8 each): myocardial infarction (MI) group, EPO group, MSC group and MSC-EPO group. MI was made by ligating the anterior descending coronary artery. MSC was injected in the infarcted area immediately after ligation in MSC group and MSC-EPO group. EPO (3000 U/kg) was administered i.p. in EPO group and MSC-EPO group for 3 days post MI and on the 14th to 16th day post MI. Cardiac function was measured by echocardiography at 2 and 21 days after MI. MI size was measured, and the level of phosphorylated Akt was assessed by Western blot and immunohistology at 21 days post MI.


RESULTS
LVEF was significantly lower at 21 days than that at 2 days in MI group while significantly increased in other 3 groups, especially in MSC-EPO group at 21 days than that at 2 days. MI size was significantly lower (20.7%+/-2.3% vs. 24.0%+/-2.3%, 26.0%+/-0.9%, 28.1%+/-1.5%, all P<0.05), capillary density was significantly higher (12.95+/-2.11 vs. 10.78+/-0.99, 10.43+/-1.52 and 6.31+/-0.69, all P<0.05) in MSC-EPO group at 21 days than that in other groups and the ratio of phosphorylated Akt to total Akt measured by Western blot was also significantly higher in MSC-EPO group than other groups (0.36 vs. 0.32, 0.31 and 0.28, all P<0.05). Compared to other groups, Bcl-2 was significantly up-regulated and Bax down-regulated in MSC-EPO group.


CONCLUSIONS
Our results demonstrated that MSC transplantation and EPO infusion could improve cardiac function and EPO enhances the therapeutic potency of MSC transplantation via PI3-K/Akt pathways.
Zhang
Ding-guo
DG
Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
Zhang
Fu-min
FM
Zhang
Yu-qing
YQ
Zhou
Fang
F
Gao
Xiang
X
Li
Chuan-fu
CF
Cao
Ke-jiang
KJ
D000818:Animals; D016026:Bone Marrow Transplantation; D004921:Erythropoietin / Q000627:therapeutic use*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D009203:Myocardial Infarction / Q000473:pathology* / Q000628:therapy; D009389:Neovascularization, Pathologic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt