Abstract

1. Cardiotoxicity is an important factor that limits the clinical use of doxorubicin (Dox). Metallothionein (MT) can antagonize the Dox-induced cardiotoxicity. Using a proteomics approach we have detected that major peroxiredoxins (Prxs) may be involved in this process. In the present study, we further investigate the mechanisms of the MT effects against Dox-induced cytotoxicity and the interactions between MT and Prxs.2. We have established a primary cardiomyocyte culture system from MT-I/II null (MT−/−) and corresponding wild type (MT+/+) neonatal mice, and pretreated the MT+/+ cardiomyocytes with ZnCl2 to establish the MT overexpression cardiomyocyte model.3. Based on the results, in MT+/+ cardiomyocytes, ZnCl2 pretreatment significantly increased the cardiomyocytes MT levels and inhibited the cardiotoxicity of Dox; it can resist LDH leakage, cardiomyocyte apoptosis, DNA damage, ROS accumulation and inhibit the decrease in activity of antioxidant enzymes induced by Dox. Moreover, ZnCl2 enhanced the expression of Prx-2, -3, -5 and -6, it can inhibit the expression of Prxs decrease in MT+/+ cardiomyocytes induced by Dox, but had no effect in MT−/− cardiomyocytes.4. Therefore, the present study suggests that ZnCl2 can protect the cardiomyocytes from the Dox-induced oxidative injury and can inhibit the changes in Prxs expression through induced MT overexpression.

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