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

Acta Pharmacol Sin. 2020 May;41(5):638-649. doi: 10.1038/s41401-019-0320-y. Epub 2019 Nov 25.


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.

Keywords: Nrf2; Zinc; ZnPP; cadmium toxicity; engineered cardiac tissue; heme oxygenase-1; metallothionein.

MeSH terms

  • Animals
  • Cadmium / administration & dosage
  • Cadmium / toxicity*
  • Dose-Response Relationship, Drug
  • Metallothionein / deficiency
  • Metallothionein / genetics
  • Metallothionein / metabolism*
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Tissue Engineering*
  • Zinc / pharmacology*


  • Cadmium
  • Metallothionein
  • Zinc