Identification of hormonal role and cardiac protection from erythropoietin in adult spontaneously hypertensive rats with doxorubicin induced cardiotoxicity
Chehab, Leena Maggie
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Gender has been cited as a factor that may influence the degree of doxorubicin (dox) induced cardiotoxicity during chemotherapy. Younger females and adult males appear to be hypersensitive to the oxidative stress-induced cardiomyopathy. Our study examined whether gender affects the severity of dox induced toxicity in a spontaneously hypertensive rats (SHR) model. Groups of male and female SHR were subcutaneously implanted with a mammary adenocarcinoma cell line (SST-2) originally derived from a female SHR. Following implantation, they were treated with either 10 mg/kg dox, 50 mg/kg dezrazoxane (drz), 1000 mg/kg erythropoietin alpha (epo), or a combination of either drz or epo with dox. Male SHR experienced a larger decrease in weight and hematological toxicity when compared to female SHR. In addition, male cardiac function as measured by echocardiogram indicated a more pronounced decrease in overall cardiac function. Dox-induced increases in cTnT and total cardiac protein oxidation were also present to a greater extent in male SHR, in addition to a decrease in autophagy, when compared to female SHR. The addition of epo as a potential cardioprotectant attenuated dox toxicity in female SHR but did not mitigate the negative effects of dox in male SHR. A statistical analysis of cTnT levels and testosterone levels indicates a direct inverse relationship. The differences in the above parameters between male and female SHR indicates that gender influences dox-induced toxicity and testosterone may play a role in protection.
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