Zinc-induced metallothionein overexpression prevents doxorubicin toxicity in cardiomyocytes by regulating the peroxiredoxins

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.

• Cardiotoxicity
• doxorubicin
• metallothionein
• peroxiredoxins
• zinc

Acknowledgements

This project was supported by the National Natural Science Foundation of China (30873130 and 81202608).

Declaration of interest

The authors report no declarations of interest.