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Induction of thioredoxin reductase 1 by crotonaldehyde as an adaptive mechanism in human endothelial cells

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Abstract

Cigarette smoking is one of the main sources of toxic chemical exposure to humans and is the greatest cause of progression of vascular disease. Crotonaldehyde is one of the major constituents of cigarette smoke and a product of endogenous lipid peroxidation. Thioredoxin reductase (TrxR) is a key element of the intact thioredoxin (Trx) system, which is predominant in modulating the intracellular redox homeostasis. In this study, we showed the effects of crotonaldehyde on the induction of TrxR1 expression in human endothelial cells. Crotonaldehyde exposure caused notably increased phosphorylation of p38 mitogen-activated protein kinase (MAPK). Introduction of siRNA against nuclear factor erythroid 2-related factor 2 (Nrf2) downregulated TrxR1 expression. Furthermore, treatment with auranofin, a TrxR inhibitor, significantly increased the death rate of crotonaldehyde-exposed cells. In summary, these results suggest a role for TrxR1 upregulation through p38 MAPK-Nrf2 activation in the adaptive response of human endothelial cells to crotonaldehyde.

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References

  1. Barua, R. S. & Ambrose, J. A. Mechanisms of coronary thrombosis in cigarette smoke exposure. Arterioscler Thromb Vasc Biol 33:1460–1467 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Birrell, M. A., Wong, S., Catley, M. C. & Belvisi, M. G. Impact of tobacco-smoke on key signaling pathways in the innate immune response in lung macrophages. J Cell Physiol 214:27–37 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Rahman, M. M. & Laher, I. Structural and functional alteration of blood vessels caused by cigarette smoking: an overview of molecular mechanisms. Curr Vasc Pharmacol 5:276–292 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Yang, H. et al. Integrated analysis of miRNA and mRNA reveals that acrolein modulates GPI anchor biosynthesis in human primary endothelial cells. BioChip J 7:11–16 (2013).

    Article  CAS  Google Scholar 

  5. Zhang, Y. Q. et al. Expression profiling and pathway analysis of microRNA expression in the lungs of mice exposed to long-term, low-dose benzo(a)pyrene. Mol Cell Toxicol 10:67–74 (2014).

    Article  CAS  Google Scholar 

  6. Budiawan A & Eder, E. Detection of 1,N(2)-propanodeoxyguanosine adducts in DNA of Fischer 344 rats by an adapted (32)P-post-labeling technique after per os application of crotonaldehyde. Carcinogenesis 21: 1191–1196 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Kawaguchi-Niida, M. et al. Crotonaldehyde accumulates in glial cells of Alzheimer’s disease brain. Acta Neuropathol 111:422–429 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. IAR C. Crotonaldehyde. IARC monographs on the evaluation of carcinogenic risks to humans/World Health Organization, International Agency for Research on Cancer 63:373–391 (1995).

    Google Scholar 

  9. Eder, E., Schuler, D. & Budiawan A. Cancer risk assessment for crotonaldehyde and 2-hexenal: an approach. IARC Sci Publ 150:219–232 (1999).

    CAS  PubMed  Google Scholar 

  10. Esterbauer, H., Schaur, R. J. & Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11:81–128 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Stein, S., Lao, Y., Yang, I. Y., Hecht, S. S. & Moriya, M. Genotoxicity of acetaldehyde-and crotonaldehyde-induced 1,N2-propanodeoxyguanosine DNA adducts in human cells. Mutat Res 608:1–7 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Yang, B. C. et al. Crotonaldehyde-exposed macrophages induce IL-8 release from airway epithelial cells through NF-kappaB and AP-1 pathways. Toxicol Lett 219:26–34 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Yang, B. C. et al. Crotonaldehyde induces apoptosis in alveolar macrophages through intracellular calcium, mitochondria and p53 signaling pathways. J Toxicol Sci 38:225–235 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Pei, Z. et al. alpha,beta-Unsaturated aldehyde crotonaldehyde triggers cardiomyocyte contractile dysfunction: role of TRPV1 and mitochondrial function. Pharmacol Res 82:40–50 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Liu, X. Y., Yang, Z. H., Pan, X. J., Zhu, M. X. & Xie, J. P. Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett 197:113–122 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Holmgren, A. & Lu, J. Thioredoxin and thioredoxin reductase: current research with special reference to human disease. Biochem Biophys Res Commun 396:120–124 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Kondo, N., Nakamura, H., Masutani, H. & Yodoi, J. Redox regulation of human thioredoxin network. Antioxid Redox Signal 8:1881–1890 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Meyer, Y., Buchanan, B. B., Vignols, F. & Reichheld, J. P. Thioredoxins and glutaredoxins: unifying elements in redox biology. Annu Rev Genet 43:335–367 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Cai, W. et al. Small molecule inhibitors of mammalian thioredoxin reductase. Free Radic Biol Med 52:257–265 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Sengupta, R. & Holmgren, A. Thioredoxin and thioredoxin reductase in relation to reversible S-nitrosylation. Antioxid Redox Signal 18:259–269 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Lee, S. E. & Park, Y. S. The role of antioxidant enzymes in adaptive responses to environmental toxicants in vascular disease. Mol Cell Toxicol 9:95–101 (2013).

    Article  CAS  Google Scholar 

  22. Branco, V., Canario, J., Lu, J., Holmgren, A. & Carvalho, C. Mercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase. Free Radic Biol Med 52:781–793 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Cunniff, B. et al. Resolution of oxidative stress by thioredoxin reductase: Cysteine versus selenocysteine. Redox Biol 2:475–484 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Arner, E. S. & Holmgren, A. The thioredoxin system in cancer-introduction to a thematic volume of Seminars in Cancer Biology. Semin Cancer Biol 16:419 (2006).

    Article  PubMed  Google Scholar 

  25. Jan, Y. H. et al. Acetaminophen reactive intermediates target hepatic thioredoxin reductase. Chem Res Toxicol 27:882–894 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fan, C. et al. Enhancement of auranofin-induced lung cancer cell apoptosis by selenocystine, a natural inhibitor of TrxR1 in vitro and in vivo. Cell Death Dis 5:e1191 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lu, J. & Holmgren, A. The thioredoxin antioxidant system. Free Radic Biol Med 66:75–87 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Nguyen, T., Nioi, P. & Pickett, C. B. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291–13295 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wakabayashi, N., Slocum, S. L., Skoko, J. J., Shin, S. & Kensler, T. W. When NRF2 Talks, Who’s Listening? Antioxid Redox Signal 13:1649–1663 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Anestal, K., Prast-Nielsen, S., Cenas, N. & Arner, E. S. J. Cell Death by SecTRAPs: Thioredoxin Reductase as a Prooxidant Killer of Cells. PLoS ONE 3:e1846 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu, C. R. et al. Enhancement of Auranofin-Induced Apoptosis in MCF-7 Human Breast Cells by Selenocystine, a Synergistic Inhibitor of Thioredoxin Reductase. PLoS ONE 8:e53945 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schalkwijk, C. G. & Stehouwer, C. D. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond) 109:143–159 (2005).

    Article  CAS  Google Scholar 

  33. Park, H. R., Yang, H., Kim, G. D., Son, G. W. & Park, Y. S. Microarray analysis of gene expression in 3-methylcholanthrene-treated human endothelial cells. Mol Cell Toxicol 10:19–27 (2014).

    Article  CAS  Google Scholar 

  34. Sumpio, B. E., Riley, J. T. & Dardik, A. Cells in focus: endothelial cell. Int J Biochem Cell Biol 34:1508–1512 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Sena, C. M., Pereira, A. M. & Seica, R. Endothelial dysfunction -A major mediator of diabetic vascular disease. Biochimica Et Biophysica Acta-Molecular Basis of Disease 1832:2216–2231 (2013).

    Article  CAS  Google Scholar 

  36. Rajendran, P. et al. The vascular endothelium and human diseases. Int J Biol Sci 9:1057–1069 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Park, Y. S. et al. Acrolein induces cyclooxygenase-2 and prostaglandin production in human umbilical vein endothelial cells: roles of p38 MAP kinase. Arterioscler Thromb Vasc Biol 27:1319–1325 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Haussmann, H. J. Use of Hazard Indices for a Theoretical Evaluation of Cigarette Smoke Composition. Chem Res Toxicol 25:794–810 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Bein, K. & Leikauf, G. D. Acrolein -a pulmonary hazard. Mol Nutr Food Res 55:1342–1360 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Luczaj, W. & Skrzydlewska, E. DNA damage caused by lipid peroxidation products. Cell Mol Biol Lett 8: 391–413 (2003).

    CAS  PubMed  Google Scholar 

  41. Liu, X. Y., Yang, Z. H., Pan, X. J., Zhu, M. X. & Xie, J. P. Crotonaldehyde induces oxidative stress and caspase-dependent apoptosis in human bronchial epithelial cells. Toxicol Lett 195:90–98 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Arner, E. S. J. Focus on mammalian thioredoxin reductases -Important selenoproteins with versatile functions. Biochimica Et Biophysica Acta-General Subjects 1790:495–526 (2009).

    Article  CAS  Google Scholar 

  43. Lu, J. et al. Inhibition of mammalian thioredoxin reductase by some flavonoids: Implications for myricetin and quercetin anticancer activity. Cancer Research 66:4410–4418 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Sakurai, A. et al. Transcriptional regulation of thioredoxin reductase 1 expression by cadmium in vascular endothelial cells: role of NF-E2-related factor-2. J Cell Physiol 203:529–537 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Altschmied, J. & Haendeler, J. Thioredoxin-1 and Endothelial Cell Aging: Role in Cardiovascular Diseases. Antioxidants & Redox Signaling 11:1733–1740 (2009).

    Article  CAS  Google Scholar 

  46. Choi, H., Tostes, R. C. & Webb, R. C. Thioredoxin reductase inhibition reduces relaxation by increasing oxidative stress and s-nitrosylation in mouse aorta. J Cardiovasc Pharmacol 58:522–527 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fernando, M. R., Nanri, H., Yoshitake, S., Nagata-Kuno, K. & Minakami, S. Thioredoxin regenerates proteins inactivated by oxidative stress in endothelial cells. Eur J Biochem 209:917–922 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Yang, H. et al. An integrated analysis of microRNA and mRNA expression in salvianolic acid B-treated human umbilical vein endothelial cells. Mol Cell Toxicol 9:1–7 (2013).

    Article  CAS  Google Scholar 

  49. Son, G. W., Kim, G. D., Yang, H., Park, H. R. & Park, Y. S. Alteration of Gene Expression Profile by Melatonin in Endothelial Cells. BioChip J 8:91–101 (2014).

    Article  CAS  Google Scholar 

  50. Cho, Y., Song, M. K., Choi, H. S. & Ryu, J. C. Analysis of Dose-Response to Hexanal-Induced Gene Expression in A549 Human Alveolar Cells. BioChip J 8: 75–82 (2014).

    Article  CAS  Google Scholar 

  51. Lee, S. E. et al. Upregulation of heme oxygenase-1 as an adaptive mechanism for protection against crotonaldehyde in human umbilical vein endothelial cells. Toxicol Lett 201:240–248.

  52. Park, H. R., Lee, S. E., Yang, H., Son, G. W. & Park, Y. S. Functional Screening of Altered MicroRNA Expression in 3-methylcholanthrene-treated Human Umbilical Vein Endothelial Cells. BioChip J 8:260–268 (2014).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology and School of Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Korea

    Seung Eun Lee, Gun Woo Son, Hye Rim Park, Cheung-Seog Park & Yong Seek Park

  2. Department of Physiology, School of Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Korea

    Young-Ho Jin

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  1. Seung Eun Lee
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  2. Gun Woo Son
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Correspondence to Yong Seek Park.

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Lee, S.E., Son, G.W., Park, H.R. et al. Induction of thioredoxin reductase 1 by crotonaldehyde as an adaptive mechanism in human endothelial cells. Mol. Cell. Toxicol. 11, 433–439 (2015). https://doi.org/10.1007/s13273-015-0046-y

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  • DOI: https://doi.org/10.1007/s13273-015-0046-y

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