Journal of Molecular Medicine

, Volume 84, Issue 12, pp 997–1003 | Cite as

Thioredoxin in the cardiovascular system

  • Cameron J. World
  • Hideyuki Yamawaki
  • Bradford C. Berk


The thioredoxin (TRX) system (TRX, TRX reductase, and NADPH) is a ubiquitous thiol oxidoreductase system that regulates cellular reduction/oxidation (redox) status. The impairment of cell redox state alters multiple cell pathways, which may contribute to the pathogenesis of cardiovascular disorders including hypertension, atherosclerosis, and heart failure. In this manuscript, we review the essential roles that TRX plays by limiting oxidative stress directly via antioxidant effects and indirectly by protein–protein interactions with key signaling molecules such as thioredoxin interacting protein (TXNIP). TRX and its endogenous regulators may represent important future targets to develop clinical therapies for diseases associated with oxidative stress.


Antioxidants Cardiovascular diseases Endothelium Smooth muscle Signal transduction 



Apoptosis signal-regulating kinase 1


Endothelial cell


Jun N-terminal kinase


Platelet-derived growth factor


Reactive oxygen species




TRX-interacting protein


Vascular cell adhesion molecule


Vascular smooth muscle cell



This study was supported by the NIH grants (HL-62826 and HL-64839) to BCB.


  1. 1.
    Nordberg J, Arner ES (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 31:1287–1312PubMedCrossRefGoogle Scholar
  2. 2.
    Powis G, Briehl M, Oblong J (1995) Redox signalling and the control of cell growth and death. Pharmacol Ther 68:149–173PubMedCrossRefGoogle Scholar
  3. 3.
    Chae HZ, Chung SJ, Rhee SG (1994) Thioredoxin-dependent peroxide reductase from yeast. J Biol Chem 269:27670–27678PubMedGoogle Scholar
  4. 4.
    Kang SW, Chae HZ, Seo MS, Kim K, Baines IC, Rhee SG (1998) Mammalian peroxiredoxin isoforms can reduce hydrogen peroxide generated in response to growth factors and tumor necrosis factor-alpha. J Biol Chem 273:6297–6302PubMedCrossRefGoogle Scholar
  5. 5.
    Spyrou G, Enmark E, Miranda-Vizuete A, Gustafsson J (1997) Cloning and expression of a novel mammalian thioredoxin. J Biol Chem 272:2936–2941PubMedCrossRefGoogle Scholar
  6. 6.
    Tanaka T, Hosoi F, Yamaguchi-Iwai Y, Nakamura H, Masutani H, Ueda S, Nishiyama A, Takeda S, Wada H, Spyrou G et al (2002) Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosis. Embo J 21:1695–1703PubMedCrossRefGoogle Scholar
  7. 7.
    Matthews JR, Wakasugi N, Virelizier JL, Yodoi J, Hay RT (1992) Thioredoxin regulates the DNA binding activity of NF-kappa B by reduction of a disulphide bond involving cysteine 62. Nucleic Acids Res 20:3821–3830PubMedGoogle Scholar
  8. 8.
    Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, Yodoi J (1997) AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc Natl Acad Sci USA 94:3633–3638PubMedCrossRefGoogle Scholar
  9. 9.
    Powis G, Mustacich D, Coon A (2000) The role of the redox protein thioredoxin in cell growth and cancer. Free Radic Biol Med 29:312–322PubMedCrossRefGoogle Scholar
  10. 10.
    Okuda M, Inoue N, Azumi H, Seno T, Sumi Y, Hirata K, Kawashima S, Hayashi Y, Itoh H, Yodoi J et al (2001) Expression of glutaredoxin in human coronary arteries: its potential role in antioxidant protection against atherosclerosis. Arterioscler Thromb Vasc Biol 21:1483–1487PubMedGoogle Scholar
  11. 11.
    Nakamura H, Matsuda M, Furuke K, Kitaoka Y, Iwata S, Toda K, Inamoto T, Yamaoka Y, Ozawa K, Yodoi J (1994) Adult T cell leukemia-derived factor/human thioredoxin protects endothelial F-2 cell injury caused by activated neutrophils or hydrogen peroxide. Immunol Lett 42:75–80PubMedCrossRefGoogle Scholar
  12. 12.
    Haendeler J, Hoffmann J, Zeiher AM, Dimmeler S (2004) Antioxidant effects of statins via S-nitrosylation and activation of thioredoxin in endothelial cells: a novel vasculoprotective function of statins. Circulation 110:856–861PubMedCrossRefGoogle Scholar
  13. 13.
    Schulze PC, De Keulenaer GW, Yoshioka J, Kassik KA, Lee RT (2002) Vitamin D3-upregulated protein-1 (VDUP-1) regulates redox-dependent vascular smooth muscle cell proliferation through interaction with thioredoxin. Circ Res 91:689–695PubMedCrossRefGoogle Scholar
  14. 14.
    Takagi Y, Gon Y, Todaka T, Nozaki K, Nishiyama A, Sono H, Hashimoto N, Kikuchi H, Yodoi J (1998) Expression of thioredoxin is enhanced in atherosclerotic plaques and during neointima formation in rat arteries. Lab Invest 78:957–966PubMedGoogle Scholar
  15. 15.
    Furman C, Rundlof AK, Larigauderie G, Jaye M, Bricca G, Copin C, Kandoussi AM, Fruchart JC, Arner ES, Rouis M (2004) Thioredoxin reductase 1 is upregulated in atherosclerotic plaques: specific induction of the promoter in human macrophages by oxidized low-density lipoproteins. Free Radic Biol Med 37:71–85PubMedCrossRefGoogle Scholar
  16. 16.
    Tanito M, Nakamura H, Kwon YW, Teratani A, Masutani H, Shioji K, Kishimoto C, Ohira A, Horie R, Yodoi J (2004) Enhanced oxidative stress and impaired thioredoxin expression in spontaneously hypertensive rats. Antioxid Redox Signal 6:89–97PubMedCrossRefGoogle Scholar
  17. 17.
    Yamagata K, Tagami M, Ikeda K, Yamori Y, Nara Y (2000) Altered gene expressions during hypoxia and reoxygenation in cortical neurons isolated from stroke-prone spontaneously hypertensive rats. Neurosci Lett 284:131–134PubMedCrossRefGoogle Scholar
  18. 18.
    Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:C1424–1437PubMedGoogle Scholar
  19. 19.
    Turoczi T, Chang VW, Engelman RM, Maulik N, Ho YS, Das DK (2003) Thioredoxin redox signaling in the ischemic heart: an insight with transgenic mice overexpressing Trx1. J Mol Cell Cardiol 35:695–704PubMedCrossRefGoogle Scholar
  20. 20.
    Yamamoto M, Yang G, Hong C, Liu J, Holle E, Yu X, Wagner T, Vatner SF, Sadoshima J (2003) Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy. J Clin Invest 112:1395–1406PubMedCrossRefGoogle Scholar
  21. 21.
    Kuster GM, Pimentel DR, Adachi T, Ido Y, Brenner DA, Cohen RA, Liao R, Siwik DA, Colucci WS (2005) Alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes is mediated via thioredoxin-1-sensitive oxidative modification of thiols on Ras. Circulation 111:1192–1198PubMedCrossRefGoogle Scholar
  22. 22.
    Aota M, Matsuda K, Isowa N, Wada H, Yodoi J, Ban T (1996) Protection against reperfusion-induced arrhythmias by human thioredoxin. J Cardiovasc Pharmacol 27:727–732PubMedCrossRefGoogle Scholar
  23. 23.
    Shioji K, Kishimoto C, Nakamura H, Masutani H, Yuan Z, Oka S, Yodoi J (2002) Overexpression of thioredoxin-1 in transgenic mice attenuates adriamycin-induced cardiotoxicity. Circulation 106:1403–1409PubMedCrossRefGoogle Scholar
  24. 24.
    Liu W, Nakamura H, Shioji K, Tanito M, Oka S, Ahsan MK, Son A, Ishii Y, Kishimoto C, Yodoi J (2004) Thioredoxin-1 ameliorates myosin-induced autoimmune myocarditis by suppressing chemokine expressions and leukocyte chemotaxis in mice. Circulation 110:1276–1283PubMedCrossRefGoogle Scholar
  25. 25.
    Tao L, Gao E, Bryan NS, Qu Y, Liu HR, Hu A, Christopher TA, Lopez BL, Yodoi J, Koch WJ et al (2004) Cardioprotective effects of thioredoxin in myocardial ischemia and the reperfusion role of S-nitrosation. Proc Natl Acad Sci USA 101:11471–11476PubMedCrossRefGoogle Scholar
  26. 26.
    Haendeler J, Hoffmann J, Tischler V, Berk BC, Zeiher AM, Dimmeler S (2002) Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69. Nat Cell Biol 4:743–749PubMedCrossRefGoogle Scholar
  27. 27.
    Nakamura H, De Rosa S, Roederer M, Anderson MT, Dubs JG, Yodoi J, Holmgren A, Herzenberg LA (1996) Elevation of plasma thioredoxin levels in HIV-infected individuals. Int Immunol 8:603–611PubMedGoogle Scholar
  28. 28.
    Yoshida S, Katoh T, Tetsuka T, Uno K, Matsui N, Okamoto T (1999) Involvement of thioredoxin in rheumatoid arthritis: its costimulatory roles in the TNF-alpha-induced production of IL-6 and IL-8 from cultured synovial fibroblasts. J Immunol 163:351–358PubMedGoogle Scholar
  29. 29.
    Kishimoto C, Shioji K, Nakamura H, Nakayama Y, Yodoi J, Sasayama S (2001) Serum thioredoxin (TRX) levels in patients with heart failure. Jpn Circ J 65:491–494PubMedCrossRefGoogle Scholar
  30. 30.
    Jekell A, Hossain A, Alehagen U, Dahlstrom U, Rosen A (2004) Elevated circulating levels of thioredoxin and stress in chronic heart failure. Eur J Heart Fail 6:883–890PubMedGoogle Scholar
  31. 31.
    Miyamoto M, Kishimoto C, Shioji K, Lee JD, Shimizu H, Ueda T, Yodoi J (2003) Cutaneous arteriolar thioredoxin expression in patients with heart failure. Circ J 67:116–118PubMedCrossRefGoogle Scholar
  32. 32.
    Miyamoto M, Kishimoto C, Nimata M, Nakamura H, Yodoi J (2004) Thioredoxin, a redox-regulating protein, is expressed in spontaneous myocarditis in inbred strains of mice. Int J Cardiol 95:315–319PubMedCrossRefGoogle Scholar
  33. 33.
    Hokamaki J, Kawano H, Soejima H, Miyamoto S, Kajiwara I, Kojima S, Sakamoto T, Sugiyama S, Yoshimura M, Nakamura H et al (2005) Plasma thioredoxin levels in patients with unstable angina. Int J Cardiol 99:225–231PubMedCrossRefGoogle Scholar
  34. 34.
    Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275:90–94PubMedCrossRefGoogle Scholar
  35. 35.
    Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. Embo J 17:2596–2606PubMedCrossRefGoogle Scholar
  36. 36.
    Chen KS, DeLuca HF (1994) Isolation and characterization of a novel cDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3. Biochim Biophys Acta 1219:26–32PubMedGoogle Scholar
  37. 37.
    Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, Takagi Y, Sono H, Gon Y, Yodoi J (1999) Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem 274:21645–21650PubMedCrossRefGoogle Scholar
  38. 38.
    Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, Kim DK, Lee KW, Han PL, Rhee SG et al (2000) Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol 164:6287–6295PubMedGoogle Scholar
  39. 39.
    Schulze PC, Yoshioka J, Takahashi T, He Z, King GL, Lee RT (2004) Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein. J Biol Chem 279:30369–30374PubMedCrossRefGoogle Scholar
  40. 40.
    Yoshioka J, Schulze PC, Cupesi M, Sylvan JD, MacGillivray C, Gannon J, Huang H, Lee RT (2004) Thioredoxin-interacting protein controls cardiac hypertrophy through regulation of thioredoxin activity. Circulation 109:2581–2586PubMedCrossRefGoogle Scholar
  41. 41.
    Yamawaki H, Pan S, Lee RT, Berk BC (2005) Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells. J Clin Invest 115:733–738PubMedCrossRefGoogle Scholar
  42. 42.
    Yamawaki H, Lehoux S, Berk BC (2003) Chronic physiological shear stress inhibits tumor necrosis factor-induced proinflammatory responses in rabbit aorta perfused ex vivo. Circulation 108:1619–1625PubMedCrossRefGoogle Scholar
  43. 43.
    Butler LM, Zhou X, Xu WS, Scher HI, Rifkind RA, Marks PA, Richon VM (2002) The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci USA 99:11700–11705PubMedCrossRefGoogle Scholar
  44. 44.
    Cheng GC, Schulze PC, Lee RT, Sylvan J, Zetter BR, Huang H (2004) Oxidative stress and thioredoxin-interacting protein promote intravasation of melanoma cells. Exp Cell Res 300:297–307PubMedCrossRefGoogle Scholar
  45. 45.
    Minn AH, Hafele C, Shalev A (2005) Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces beta-cell apoptosis. Endocrinology 146:2397–2405PubMedCrossRefGoogle Scholar
  46. 46.
    Wang Z, Rong YP, Malone MH, Davis MC, Zhong F, Distelhorst CW (2006) Thioredoxin-interacting protein (txnip) is a glucocorticoid-regulated primary response gene involved in mediating glucocorticoid-induced apoptosis. Oncogene 25:1903–1913PubMedCrossRefGoogle Scholar
  47. 47.
    Saitoh T, Tanaka S, Koike T (2001) Rapid induction and Ca2+ influx-mediated suppression of vitamin D3 up-regulated protein 1 (VDUP1) mRNA in cerebellar granule neurons undergoing apoptosis. J Neurochem 78:1267–1276PubMedCrossRefGoogle Scholar
  48. 48.
    Wang Y, De Keulenaer GW, Lee RT (2002) Vitamin D(3)-up-regulated protein-1 is a stress-responsive gene that regulates cardiomyocyte viability through interaction with thioredoxin. J Biol Chem 277:26496–26500PubMedCrossRefGoogle Scholar
  49. 49.
    Minn AH, Pise-Masison CA, Radonovich M, Brady JN, Wang P, Kendziorski C, Shalev A (2005) Gene expression profiling in INS-1 cells overexpressing thioredoxin-interacting protein. Biochem Biophys Res Commun 336:770–778PubMedCrossRefGoogle Scholar
  50. 50.
    Xiang G, Seki T, Schuster MD, Witkowski P, Boyle AJ, See F, Martens TP, Kocher A, Sondermeijer H, Krum H et al (2005) Catalytic degradation of vitamin D up-regulated protein 1 mRNA enhances cardiomyocyte survival and prevents left ventricular remodeling after myocardial ischemia. J Biol Chem 280:39394–39402PubMedCrossRefGoogle Scholar
  51. 51.
    Dutta KK, Nishinaka Y, Masutani H, Akatsuka S, Aung TT, Shirase T, Lee WH, Yamada Y, Hiai H, Yodoi J et al (2005) Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis. Lab Invest 85:798–807PubMedCrossRefGoogle Scholar
  52. 52.
    Han SH, Jeon JH, Ju HR, Jung U, Kim KY, Yoo HS, Lee YH, Song KS, Hwang HM, Na YS et al (2003) VDUP1 upregulated by TGF-beta1 and 1,25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression. Oncogene 22:4035–4046PubMedCrossRefGoogle Scholar
  53. 53.
    Jeon JH, Lee KN, Hwang CY, Kwon KS, You KH, Choi I (2005) Tumor suppressor VDUP1 increases p27(kip1) stability by inhibiting JAB1. Cancer Res 65:4485–4489PubMedCrossRefGoogle Scholar
  54. 54.
    Nishinaka Y, Nishiyama A, Masutani H, Oka S, Ahsan KM, Nakayama Y, Ishii Y, Nakamura H, Maeda M, Yodoi J (2004) Loss of thioredoxin-binding protein-2/vitamin D3 up-regulated protein 1 in human T-cell leukemia virus type I-dependent T-cell transformation: implications for adult T-cell leukemia leukemogenesis. Cancer Res 64:1287–1292PubMedCrossRefGoogle Scholar
  55. 55.
    Nishinaka Y, Masutani H, Oka S, Matsuo Y, Yamaguchi Y, Nishio K, Ishii Y, Yodoi J (2004) Importin alpha1 (Rch1) mediates nuclear translocation of thioredoxin-binding protein-2/vitamin D(3)-up-regulated protein 1. J Biol Chem 279:37559–37565PubMedCrossRefGoogle Scholar
  56. 56.
    Escrich E, Moral R, Garcia G, Costa I, Sanchez JA, Solanas M (2004) Identification of novel differentially expressed genes by the effect of a high-fat n-6 diet in experimental breast cancer. Mol Carcinog 40:73–78PubMedCrossRefGoogle Scholar
  57. 57.
    Ohta S, Lai EW, Pang AL, Brouwers FM, Chan WY, Eisenhofer G, de Krijger R, Ksinantova L, Breza J, Blazicek P et al (2005) Down-regulation of metastasis suppressor genes in malignant pheochromocytoma. Int J Cancer 114:139–143PubMedCrossRefGoogle Scholar
  58. 58.
    Mizuno K, Tokumasu A, Nakamura A, Hayashi Y, Kojima Y, Kohri K, Noce T (2006) Genes associated with the formation of germ cells from embryonic stem cells in cultures containing different glucose concentrations. Mol Reprod Dev 73:437–445PubMedCrossRefGoogle Scholar
  59. 59.
    Hui TY, Sheth SS, Diffley JM, Potter DW, Lusis AJ, Attie AD, Davis RA (2004) Mice lacking thioredoxin-interacting protein provide evidence linking cellular redox state to appropriate response to nutritional signals. J Biol Chem 279:24387–24393PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Cameron J. World
    • 1
  • Hideyuki Yamawaki
    • 2
  • Bradford C. Berk
    • 1
  1. 1.Cardiovascular Research Institute, Department of MedicineUniversity of RochesterRochesterUSA
  2. 2.Department of Epidemiology, Research InstituteNational Cardiovascular CenterOsakaJapan

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