title: Erythropoietin modulates imbalance of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in doxorubicin-induced cardiotoxicity.
abstract: BACKGROUND
  Doxorubicin (DOX) is a highly effective anti-cancer drug with limited clinical use due to its serious cardiotoxicity. Recent studies reported that erythropoietin (EPO) could exert a cardioprotective effect by non-erythropoietic effects. This study was to investigate fibrosis of DOX-induced cardiotoxicity and determine mechanisms of EPO against extracellular matrix (ECM) remodelling.
  
  
  METHODS
  Rats were grouped as the control group, the DOX group and the DOX+EPO group. DOX (2.5 mg/kg/dose, six doses for two weeks) was administered to induce cardiotoxicity by intraperitoneal injections in the DOX group and the DOX+EPO group, and EPO (2500U/kg/dose, six doses for two weeks) was administered simultaneously in the DOX+EPO group. Two weeks after the last administration, rats were killed with cardiac tissues used for histological analyses and immunological detections for matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2).
  
  
  RESULTS
  Rats treated with DOX showed degenerative changes with cardiac fibrosis. Compared to the control group, the expression of MMP-2 was up-regulated whereas that of TIMP-2 was down-regulated in the DOX group. EPO administration improved cardiac fibrosis, decreased MMP-2 expression, increased TIMP-2 expression and ameliorated imbalance of MMP-2/TIMP-2 ratio.
  
  
  CONCLUSIONS
  The present study suggests that EPO can exert a cardioprotective effect on DOX-induced cardiotoxicity which may be associated with improving MMP-2/TIMP-2 imbalance.
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Guangdong Women and Children Hospital, Guangzhou 510010, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Cardiology, General Hospital of Tianjin Medical University, Tianjin 300052, China.
authors.forename: Peixian
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China. Electronic address: geriatricsxu@163.com.
authors.forename: Miqing
authors.initials: M
authors.lastname: Xu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D054715:Cardiotoxins / Q000009:adverse effects / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D004921:Erythropoietin / Q000494:pharmacology*; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D054715:Cardiotoxins; D004921:Erythropoietin; D019716:Tissue Inhibitor of Metalloproteinase-2; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
keywords: Cardiotoxicity; Doxorubicin; Erythropoietin; Fibrosis; Matrix metalloproteinase; Tissue inhibitor of metalloproteinase