Nfe2 expression in the hyperthyroid rat heart receiving doxorubicin

Abstract

The most evidence suggests that the major cause of doxorubicin (DOX) cardiotoxicity is reactive oxygen species and consequently oxidative stress. The accumulation of oxidative damages leading to mitochondrial dysfunction results in contractility disorders. In a cell adaptive process against oxidative stress, the transcription factor Nrf2 (Nfe2) plays a crucial role by stimulating expression of genes controlling synthesis of enzymes taking part in oxidative defence and red-ox equilibrium, e.g. glucose-6-phosphate dehydrogenase, phosphogluconate dehydrogenase and malic enzyme. Expression of genes responsible for the synthesis of these enzymes is controlled by iodothyronine hormones. These facts lead to an assumption that the impact of anthracyclines on oxidative stress may differ in hyperthyroid and euthyroid individuals. In these studies first of all we tested the hypothesis that symptoms of oxidative stress may be evident long time since last dose of DOX and if hypothyreosis may change myocardium antioxidative response in rats which received DOX. There was no statistical difference in Nfe2 expression in hearts of rats after doxorubicin administrations (group of DOX) versus controls. In this group there were no statistical differences in cardiac NADPH and total mitochondrial glutathione concentrations and GSH/GSSG ratio comparing to the controls. Moreover, any changes in all tested parameters were observed between DOX vs. DOX+4T4. We concluded that after three weeks since last doxorubicin administration there were no significant signs of oxidative stress in the heart, and that in our study conditions there was no interaction of DOX and thyroxin referring to oxidative stress in the myocardium.