Preventive cardioprotection of erythropoietin against doxorubicin-induced cardiomyopathy.
BACKGROUND
Doxorubicin (DOX) is a highly effective chemotherapeutic agent related to dose-dependent cardiomyopathy. Recent evidence suggests that erythropoietin (EPO) can play a protective role in cardiovascular diseases by non-erythropoietic effects. In the present study, we tested the hypothesis that EPO may protect against DOX-induced cardiomyopathy through anti-apoptotic mechanisms both in vitro and in vivo.


METHODS
Isolated neonatal Wistar rat cardiomyocytes were treated with vehicle, DOX with or without EPO, or EPO. Twenty-four hours later, the cells were used to determine cardiomyocyte apoptosis (TUNEL assay). Cardiomyopathy was induced in Wistar rats by intraperitoneal injections (IP) of DOX (2.5 mg/kg, six times for 2 weeks). EPO (2,500 U/kg, six times for 2 weeks) was administered simultaneously in the DOX+EPO group and the EPO group. Two weeks after the last administration, cardiac function was evaluated by echocardiography and invasive haemodynamic measurements. Rats were then sacrificed for histological and TUNEL analyses, with immunological detection for cardiac Troponin-T (cTnT), alpha-actinin, Bax and Bcl-2.


RESULTS
EPO significantly ameliorated DOX-induced apoptosis of cultured cardiomyocytes as demonstrated by TUNEL assay. In the rat model, cardiac function significantly decreased in the DOX group. In contrast, the DOX+EPO group showed considerable improvement in cardiac function, inhibition of cardiomyocyte apoptosis, reduction of fibrosis, as well as up-regulation of Bcl-2 protein expression.


CONCLUSIONS
Our results suggest that EPO exerts preventive cardioprotective effects on DOX-induced cardiomyopathy via anti-apoptotic pathways. The up-regulation of Bcl-2 protein expression may contribute to this.
Chen
Xing
X
Department of Cardiology, General Hospital of Tianjin Medical University, Tianjin, China.
Chen
Yongli
Y
Bi
Yanyong
Y
Fu
Naikuan
N
Shan
Chunyan
C
Wang
Sili
S
Aslam
Shahid
S
Wang
Peixian Wang
PW
Xu
Jing
J
D000185:Actinin / Q000032:analysis / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D004452:Echocardiography; D004921:Erythropoietin / Q000627:therapeutic use*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020107:Troponin T / Q000032:analysis / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000096:biosynthesis
C494828:Bax protein, rat; D002316:Cardiotonic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D020107:Troponin T; D051028:bcl-2-Associated X Protein; D000185:Actinin; D004921:Erythropoietin; D004317:Doxorubicin