Dexrazoxane protects against doxorubicininduced c

Authors: Ping Xiang Hai Yan Deng Karen Li GuoYing Huang Yuan Chen Liu Tu Pak Cheung Ng Nga Hin Pong Hailu Zhao Lei Zhang Rita Yn Tz Sung

Publish Date: 2008/04/01

Volume: 63, Issue: 2, Pages: 343-349

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Abstract

Dexrazoxane DZR a clinically approved cation chelator is effective in reducing doxorubicin DOXinduced 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 DOXinduced cardiomyopathyMale Sprague–Dawley rats received weekly DOX injection 25 mg/kg for 6 weeks with or without DZR pretreatment at a dose ratio of 201 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 analysisDOX 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 dexarazoxanetreated animals had increased levels of Akt and Erk activation whilst total Akt and Erk remained unchangedOur 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 DOXinduced cardiomyopathy and protection by DZRThis research project was support by Li Ka Shing Institute of Health Sciences Grant The Chinese University of Hong Kong Project ID 6901985 and Earmarked Grant Research Grants Council Hong Kong Special Administrative Region Project No CUHK4521/05M

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