Cruciferous dithiolethione-mediated coordinated induction of total cellular and mitochondrial antioxidants and phase 2 enzymes in human primary cardiomyocytes: Cytoprotection against oxidative/electrophilic stress and doxorubicin toxicity

Hong Zhu, Zhenquan Jia, Kequan Zhou, Hara P. Misra, Arben Santo, Kathleen L. Gabrielson, Yunbo Li

Research output: Contribution to journalArticlepeer-review

Abstract

3H-1,2-dithiole-3-thione (D3T), a cruciferous organosulfur compound, induces cytoprotective enzymes in animal cardiovascular cells. However, it remains unknown if D3T also upregulates antioxidants and phase 2 enzymes in human cardiomyocytes, and protects against cell injury induced by oxidative/electrophilic species as well as doxorubicin. In this study, we found that D3T (10-50 μM) potently induced a series of antioxidants and phase 2 enzymes in primary cultured human cardiomyocytes, including superoxide dismutase (SOD), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx) glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), aldose reductase (AR), and heme oxygenase (HO). D3T treatment also caused elevation of SOD, GSH, GR, GPx and GST in the isolated mitochondria. We also observed a time-dependent induction by D3T of mRNA expression for Cu,ZnSOD, MnSOD, γ-glutamylcysteine ligase, GR, GSTA1, GSTM1, NQO1, AR, and HO-1. Pretreatment with D3T conferred concentration-dependent protection against cell injury induced by xanthine oxidase (XO)/xanthine, H2O2, 3-morpholinosydnonimine, 4-hydroxy-2-nonenal, and doxorubicin. Pretreatment with D3T also reduced the formation of intracellular reactive oxygen species by XO/xanthine, H2O2, and doxorubicin. In conclusion, this study demonstrated that D3T potently upregulated many antioxidants and phase 2 enzymes in human cardiomyocytes, which was accompanied by increased resistance to oxidative/electrophilic stress and doxorubicin toxicity.

Original languageEnglish (US)
Pages (from-to)418-429
Number of pages12
JournalExperimental Biology and Medicine
Volume234
Issue number4
DOIs
StatePublished - Apr 1 2009

Keywords

  • 3H-1,2-dithiole-3-thione
  • 4-hydroxy-2-nonenal
  • Antioxidants
  • Doxorubicin
  • Human cardiomyocytes
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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