Abstract
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 (5−20 μM) caused a dose-dependent toxicity that was detected within 8 h evidenced by suppressed beating, apoptosis, and LDH release; Zn (50−200 μM) dose-dependently induced MT expression in ECTs without causing ECT toxicity; co-treatment of ECT with Zn (50 µM) 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 (10 µM), 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 these findings towards clinical trials.
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Acknowledgements
This work was supported by 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.
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HTY designed and performed experiments, analyzed data, prepared and reviewed manuscript for submission. JZ designed and performed experiments, analyzed data, prepared and reviewed manuscript for submission. JXX prepared and reviewed manuscript for submission. LC designed experiments, prepared and reviewed manuscript for submission. JYL prepared and reviewed manuscript for submission. HLJ designed experiments, prepared and reviewed manuscript for submission. BBK designed and performed experiments, analyzed data, prepared and reviewed manuscript for submission.
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Yu, Ht., Zhen, J., Xu, Jx. et al. Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms. Acta Pharmacol Sin 41, 638–649 (2020). https://doi.org/10.1038/s41401-019-0320-y
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DOI: https://doi.org/10.1038/s41401-019-0320-y
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