Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms  

作　　者：Hai-tao Yu Juan Zhen Jian-xiang Xu Lu Cai Ji-yan Leng Hong-lei Ji Bradley B Keller 

机构地区：[1]The Pediatric Research Institute,Department of Pediatrics,University of Louisville School of Medicine,Louisville,KY 40292,USA [2]The First Hospital of Jilin University,Changchun 130021,China [3]Department of Pharmacology and Toxicology,University of Louisville,Louisville,KY 40202,USA [4]Department of Radiation Oncology,The University of Louisville School of Medicine,Louisville,KY,USA [5]Kosair Charities Pediatric Heart Research Program,Cardiovascular Innovation Institute,University of Louisville,Louisville,KY 40202,USA

出　　处：《Acta Pharmacologica Sinica》2020年第5期638-649,共12页中国药理学报（英文版）

基　　金：the Kosair Charities Pediatric Heart Research Fund to BK,the U.S-China Pediatric Research Exchange Training Program to LC and BBK,and the National Natural Science Foundation of China to HLJ(81470495);All personnel expenses and partial research-related expenses for HTY and JZ were provided by Jilin University through a collaborative research agreement between the University of Louisville and Jilin University,Changchun,China.Basic science experiments were completed at the University of Louisville,Louisville,KY,USA.

摘　　要：Cadmium(Cd)is a nonessential heavy metal and a prevalent environmental toxin that has been shown to induce significant cardiomyocyte apoptosis in neonatal murine engineered cardiac tissues(ECTs).In contrast,zinc(Zn)is a potent metallothionein(MT)inducer,which plays an important role in protection against Cd toxicity.In this study,we investigated the protective effects of Zn against Cd toxicity in ECTs and explore the underlying mechanisms.ECTs were constructed from neonatal ventricular cells of wild-type(WT)mice and mice with global MT gene deletion(MT-KO).In WT-ECTs,Cd(5−20μM)caused a dose-dependent toxicity that was detected within 8 h evidenced by suppressed beating,apoptosis,and LDH release;Zn(50−200μM)dose-dependently induced MT expression in ECTs without causing ECT toxicity;co-treatment of ECT with Zn(50µM)prevented Cd-induced toxicity.In MT-KO ECTs,Cd toxicity was enhanced;but unexpectedly,cotreatment with Zn provided partial protection against Cd toxicity.Furthermore,Cd,but not Zn,significantly activated Nrf2 and its downstream targets,including HO-1;inhibition of HO-1 by a specific HO-1 inhibitor,ZnPP(10µM),significantly increased Cd-induced toxicity,but did not inhibit Zn protection against Cd injury,suggesting that Nrf2-mediated HO-1 activation was not required for Zn protective effect.Finally,the ability of Zn to reduce Cd uptake provided an additional MT-independent mechanism for reducing Cd toxicity.Thus,Zn exerts protective effects against Cd toxicity for murine ECTs that are partially MT-mediated.Further studies are required to translate thesefindings towards clinical trials.

关 键 词：ZINC cadmium toxicity engineered cardiac tissue METALLOTHIONEIN Nrf2 heme oxygenase-1 ZNPP 

分 类 号：R965[医药卫生—药理学]