title: 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.
authors.affiliation: a School of Public Health , Capital Medical University , Beijing , PR China and.
authors.forename: Li
authors.initials: L
authors.lastname: Jing
authors.affiliation: b Evaluation and Research Center for Toxicology , Institute of Disease Control and Prevention, Academy of Military Medical Sciences , Beijing , PR China.
authors.forename: Lizhong
authors.initials: L
authors.lastname: Li
authors.affiliation: b Evaluation and Research Center for Toxicology , Institute of Disease Control and Prevention, Academy of Military Medical Sciences , Beijing , PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: b Evaluation and Research Center for Toxicology , Institute of Disease Control and Prevention, Academy of Military Medical Sciences , Beijing , PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: a School of Public Health , Capital Medical University , Beijing , PR China and.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Sun
authors.affiliation: b Evaluation and Research Center for Toxicology , Institute of Disease Control and Prevention, Academy of Military Medical Sciences , Beijing , PR China.
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054715:Cardiotoxins / Q000633:toxicity*; D002712:Chlorides / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac; D054464:Peroxiredoxins / Q000378:metabolism*; D017967:Zinc Compounds / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D054715:Cardiotoxins; D002712:Chlorides; D017967:Zinc Compounds; D004317:Doxorubicin; C016837:zinc chloride; D008668:Metallothionein; D054464:Peroxiredoxins
keywords: Cardiotoxicity; doxorubicin; metallothionein; peroxiredoxins; zinc