title: Preventive cardioprotection of erythropoietin against doxorubicin-induced cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Cardiology, General Hospital of Tianjin Medical University, Tianjin, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Yongli
authors.initials: Y
authors.lastname: Chen
authors.forename: Yanyong
authors.initials: Y
authors.lastname: Bi
authors.forename: Naikuan
authors.initials: N
authors.lastname: Fu
authors.forename: Chunyan
authors.initials: C
authors.lastname: Shan
authors.forename: Sili
authors.initials: S
authors.lastname: Wang
authors.forename: Shahid
authors.initials: S
authors.lastname: Aslam
authors.forename: Peixian Wang
authors.initials: PW
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
mesh_terms: 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
chemical_list: 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