Dexrazoxane protects against doxorubicin-induced cardiomyopathy: upregulation of Akt and Erk phosphorylation in a rat model.
OBJECTIVE
Dexrazoxane (DZR), a clinically approved cation chelator, is effective in reducing doxorubicin (DOX)-induced heart damage, yet its cardioprotective mechanism is not fully understood. We aimed to investigate the effects of DZR on the activation of Akt and Erk 1/2 signals in a rat model of DOX-induced cardiomyopathy.


METHODS
Male Sprague-Dawley rats received weekly DOX injection (2.5 mg/kg) for 6 weeks, with or without DZR pretreatment at a dose ratio of 20:1. The ventricular functions of these animals were monitored at week 6, 9 and 11 by echocardiography. At week 11, their heart morphology was studied by light and electron microscopy. Phosphorylation of Akt and Erk in heart tissues was measured by Western blot analysis.


RESULTS
DOX caused myocardial damage with compromised left ventricular function, increased myocardium injury and reduced phosphorylation of Akt and Erk. DZR exerted a significant cardioprotective effect in terms of improved fractional shortening, cardiac output and cardiomyopathy score at one or more time points. We also provided the first evidence that dexarazoxane-treated animals had increased levels of Akt and Erk activation, whilst total Akt and Erk remained unchanged.


CONCLUSIONS
Our results showed that the cardioprotective effect of dexarazoxane has been sustained beyond the treatment period. The data also suggested that activation of the Akt and Erk signaling pathways was regulated in the course of DOX-induced cardiomyopathy and protection by DZR.
Xiang
Ping
P
Department of Cardiology, Children's Hospital of Chongqing Medical University, Chongqing, China.
Deng
Hai Yan
HY
Li
Karen
K
Huang
Guo-Ying
GY
Chen
Yuan
Y
Tu
Liu
L
Ng
Pak Cheung
PC
Pong
Nga Hin
NH
Zhao
Hailu
H
Zhang
Lei
L
Sung
Rita Yn Tz
RY
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002614:Chelating Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004317:Doxorubicin / Q000009:adverse effects*; D004452:Echocardiography; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D008297:Male; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000648:ultrastructure; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000008:administration & dosage / Q000627:therapeutic use*; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D002614:Chelating Agents; D011929:Razoxane; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3