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

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.

[1]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2009, Circulation.

[2]  Masayuki Yamamoto,et al.  Nuclear Factor E2-Related Factor 2-Dependent Myocardiac Cytoprotection Against Oxidative and Electrophilic Stress , 2008, Cardiovascular Toxicology.

[3]  J. Koponen,et al.  Antioxidant gene therapy for cardiovascular disease: current status and future perspectives. , 2008, Circulation.

[4]  K. Furie,et al.  Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2008, Circulation.

[5]  D. Dobrota,et al.  Oxidative modifications of cardiac mitochondria and inhibition of cytochrome c oxidase activity by 4-hydroxynonenal , 2007, Redox report : communications in free radical research.

[6]  D. Ross,et al.  The Highly Expressed and Inducible Endogenous NAD(P)H:quinone Oxidoreductase 1 in Cardiovascular Cells Acts as a Potential Superoxide Scavenger , 2007, Cardiovascular Toxicology.

[7]  D. Jacobs,et al.  Dietary patterns, food groups and myocardial infarction: a case–control study , 2007, British Journal of Nutrition.

[8]  V. M. Víctor,et al.  Targeting antioxidants to mitochondria and cardiovascular diseases: the effects of mitoquinone. , 2007, Medical science monitor : international medical journal of experimental and clinical research.

[9]  Michael D. Green,et al.  Managing cardiotoxicity in anthracycline-treated breast cancers , 2007, Expert opinion on drug safety.

[10]  Y. J. Kang.  Antioxidant defense against anthracycline cardiotoxicity by metallothionein , 2007, Cardiovascular Toxicology.

[11]  V. Víctor,et al.  Targeting antioxidants to mitochondria: a potential new therapeutic strategy for cardiovascular diseases. , 2007, Current pharmaceutical design.

[12]  K. Furie,et al.  Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2007, Circulation.

[13]  K. Griendling,et al.  Basic mechanisms of oxidative stress and reactive oxygen species in cardiovascular injury. , 2007, Trends in cardiovascular medicine.

[14]  J. Zweier,et al.  Antioxidants and Phase 2 Enzymes in Cardiomyocytes: Chemical Inducibility and Chemoprotection Against Oxidant and Simulated Ischemia-Reperfusion Injury , 2006, Experimental biology and medicine.

[15]  Hong Zhu,et al.  Differential roles of 3H-1,2-dithiole-3-thione-induced glutathione, glutathione S-transferase and aldose reductase in protecting against 4-hydroxy-2-nonenal toxicity in cultured cardiomyocytes. , 2005, Archives of biochemistry and biophysics.

[16]  S. Yusuf,et al.  Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. , 2005, JAMA.

[17]  E. Platz,et al.  Fruit, vegetable, and antioxidant intake and all-cause, cancer, and cardiovascular disease mortality in a community-dwelling population in Washington County, Maryland. , 2004, American journal of epidemiology.

[18]  J. Mehta,et al.  Oxidative stress in cardiovascular disease: molecular basis of its deleterious effects, its detection, and therapeutic considerations , 2004, Current opinion in cardiology.

[19]  D. Ravi,et al.  Redox-cycling of anthracyclines by thioredoxin system: increased superoxide generation and DNA damage , 2004, Cancer Chemotherapy and Pharmacology.

[20]  P. Naughton,et al.  Induction of Heme Oxygenase 1 by Nitrosative Stress , 2002, The Journal of Biological Chemistry.

[21]  M. Kwak,et al.  Role of phase 2 enzyme induction in chemoprotection by dithiolethiones. , 2001, Mutation research.

[22]  D. Lefer,et al.  Oxidative stress and cardiac disease. , 2000, The American journal of medicine.

[23]  B. Van Houten,et al.  Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells. , 2000, Circulation research.

[24]  B. Kalyanaraman,et al.  Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: the role of reactive oxygen and nitrogen intermediates. , 1999, Archives of biochemistry and biophysics.

[25]  J. Zweier,et al.  Validation of Lucigenin (Bis-N-methylacridinium) as a Chemilumigenic Probe for Detecting Superoxide Anion Radical Production by Enzymatic and Cellular Systems* , 1998, The Journal of Biological Chemistry.

[26]  L. Klotz,et al.  Glutathione Peroxidase Protects against Peroxynitrite-mediated Oxidations , 1997, The Journal of Biological Chemistry.

[27]  D. S. St. Clair,et al.  The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. , 1996, The Journal of clinical investigation.

[28]  Y. J. Kang,et al.  Suppression of Doxorubicin Cardiotoxicity by Overexpression of Catalase in the Heart of Transgenic Mice (*) , 1996, The Journal of Biological Chemistry.

[29]  L. Oberley,et al.  An assay for superoxide dismutase activity in mammalian tissue homogenates. , 1989, Analytical biochemistry.

[30]  W B Jakoby,et al.  Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. , 1974, The Journal of biological chemistry.

[31]  Zhuoxiao Cao,et al.  Protecting against peroxynitrite-mediated cytotoxicity in vascular smooth muscle cells via upregulating endogenous glutathione biosynthesis by 3H-1,2-dithiole-3-thione , 2007, Cardiovascular Toxicology.

[32]  J. Hayes,et al.  Glutathione transferases. , 2005, Annual review of pharmacology and toxicology.

[33]  Kang Yj.  New understanding in cardiotoxicity. , 2003 .

[34]  H. Zhu,et al.  Characterization of benzo[a]pyrene quinone-induced toxicity to primary cultured bone marrow stromal cells from DBA/2 mice: potential role of mitochondrial dysfunction. , 1995, Toxicology and applied pharmacology.

[35]  J. Kehrer.  Free radicals as mediators of tissue injury and disease. , 1993, Critical reviews in toxicology.

[36]  L. Flohé,et al.  Assays of glutathione peroxidase. , 1984, Methods in enzymology.

[37]  H. Aebi,et al.  Catalase in vitro. , 1984, Methods in enzymology.