Targeting Cellular Antioxidant Enzymes for Treating Atherosclerotic Vascular Disease

  • Kang, Dong Hoon (Division of Life and Pharmaceutical Science and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University) ;
  • Kang, Sang Won (Division of Life and Pharmaceutical Science and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University)
  • Received : 2013.02.06
  • Accepted : 2013.03.12
  • Published : 2013.03.31


Atherosclerotic vascular dysfunction is a chronic inflammatory process that spreads from the fatty streak and foam cells through lesion progression. Therefore, its early diagnosis and prevention is unfeasible. Reactive oxygen species (ROS) play important roles in the pathogenesis of atherosclerotic vascular disease. Intracellular redox status is tightly regulated by oxidant and antioxidant systems. Imbalance in these systems causes oxidative or reductive stress which triggers cellular damage or aberrant signaling, and leads to dysregulation. Paradoxically, large clinical trials have shown that non-specific ROS scavenging by antioxidant vitamins is ineffective or sometimes harmful. ROS production can be locally regulated by cellular antioxidant enzymes, such as superoxide dismutases, catalase, glutathione peroxidases and peroxiredoxins. Therapeutic approach targeting these antioxidant enzymes might prove beneficial for prevention of ROS-related atherosclerotic vascular disease. Conversely, the development of specific antioxidant enzyme-mimetics could contribute to the clinical effectiveness.


Supported by : National Research Foundation of Korea (NRF)


  1. Abreu, I. A. and Cabelli, D. E. (2010) Superoxide dismutases-a review of the metal-associated mechanistic variations. Biochim. Biophys. Acta 1804, 263-274.
  2. Alp, N. J. and Channon, K. M. (2004) Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease. Arterioscler. Thromb. Vasc. Biol. 24, 413-420.
  3. Bedard, K. and Krause, K. H. (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87, 245-313.
  4. Blankenberg, S., Rupprecht, H. J., Bickel, C., Torzewski, M., Hafner, G., Tiret, L., Smieja, M., Cambien, F., Meyer, J. and Lackner, K. J. (2003) Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N. Engl. J. Med. 349, 1605-1613.
  5. Bliznakov, E. G. (1999) Cardiovascular diseases, oxidative stress and antioxidants: the decisive role of coenzyme Q10. Cardiovasc. Res. 43, 248-249.
  6. Chang, T., Cho, C. Park, S., Yu, S. and Kang, S. W. (2004) Peroxiredoxin III, amitochindrion-specific peroxidase, regulates apoptotic signaling by mitochondria. J. Biol. Chem. 279, 41975-41984.
  7. Chen, H., Yu, M., Li, M., Zhao, R., Zhu, Q., Zhou, W., Lu, M., Lu, Y., Zheng, T., Jiang, J., Zhao, W., Xiang, K., Jia, W. and Liu, L. (2012) Polymorphic variations in manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPX1), and catalase (CAT) contribute to elevated plasma triglyceride levels in Chinese patients with type 2 diabetes or diabetic cardiovascular disease. Mol. Cell Biochem. 363, 85-91.
  8. Choi, H. J., Kang, S. W., Yang, C. H., Rhee, S. G. and Ryu, S. E. (1998) Crystal structure of a novel human peroxidase enzyme at 2.0 A resolution. Nat. Struct. Biol. 5, 400-406.
  9. Choi, M. H., Lee, I. K., Kim, G. W., Kim, B. U., Han, Y. H., Yu, D. Y., Park, H. S., Kim, K. Y., Lee, J. S., Choi, C., Bae, Y. S., Lee, B. I., Rhee, S. G. and Kang, S. W. (2005) Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature 435, 347-353.
  10. Chu, F. F., Esworthy, R. S., Chu, P. G., Longmate, J. A., Huycke, M. M., Wilczynski, S. and Doroshow, J. H. (2004) Bacteria-induced intestinal cancer in mice with disrupted gpx1 and gpx2 genes. Cancer Res. 64, 962-968.
  11. Chu, Y., Iida, S., Lund, D. D., Weiss, R. M., DiBona, G. F., Watanabe, Y., Faraci, F. M. and Heistad, D. D. (2003) Gene transfer of extracellular superoxide dismutase reduces arterial pressure in spontaneously hypertensive rats: role of heparin-binding domain. Circ. Res. 92, 461-468.
  12. Day, B. J. (2004). Catalytic antioxidants: a radical approach to new therapeutics. Drug Discov. Today 9, 557-566.
  13. Forgione, M. A., Weiss, N., Heydrick, S., Cap, A., Klings, E. S., Bierl, C., Eberhardt, R. T., Farber, H. W. and Loscalzo, J. (2002) Cellular glutathione peroxidase deficiency and endothelial dysfunction. Am. J. Physiol. Heart Circ. Physiol. 282, H1255-1261.
  14. Fukai, T., Galis, Z. S., Meng, X. P., Parthasarathy, S. and Harrison, D. G. (1998) Vascular expression of extracellular superoxide dismutase in atherosclerosis. J. Clin. Invest. 101, 2101-2111.
  15. Gozzelino, R., Jeney, V. and Soares, M. P. (2010) Mechanisms of cell protection by heme oxygenase-1. Annu. Rev. Pharmacol. Toxicol. 50, 323-354.
  16. Griendling, K. K. (2005). ATVB in focus: redox mechanisms in blood vessels. Arterioscler. Thromb. Vasc. Biol. 25, 272-273.
  17. Guo, X., Yamada, S., Tanimoto, A., Ding, Y., Wang, K. Y., Shimajiri, S., Murata, Y., Kimura, S., Tasaki, T., Nabeshima, A., Watanabe, T., Kohno, K. and Sasaguri, Y. (2012) Overexpression of peroxiredoxin 4 attenuates atherosclerosis in apolipoprotein E knockout mice. Antioxid. Redox Signal. 17, 1362-1375.
  18. Guzik, T. J., Sadowski, J., Guzik, B., Jopek, A., Kapelak, B., Przybylowski, P., Wierzbicki, K., Korbut, R., Harrison, D. G. and Channon, K. M. (2006) Coronary artery superoxide production and nox isoform expression in human coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 26, 333-339.
  19. Imai, H. and Nakagawa, Y. (2003) Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radic. Biol. Med. 34, 145-169.
  20. Kang, S. W., Rhee, S. G., Chang, T. S., Jeong, W. and Choi, M. H. (2005) 2-Cys peroxiredoxin function in intracellular signal transduction: therapeutic implications. Trends. Mol. Med. 11, 571-578.
  21. Kisucka, J., Chauhan, A. K., Patten, I. S., Yesilaltay, A., Neumann, C., Van Etten, R. A., Krieger, M. and Wagner, D. D. (2008) Peroxiredoxin1 prevents excessive endothelial activation and early atherosclerosis. Circ. Res. 103, 598-605.
  22. Kokoszka, J. E., Coskun, P., Esposito, L. A. and Wallace, D. C. (2001) Increased mitochondrial oxidative stress in the Sod2(+/-) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis. Proc. Natl. Acad. Sci. U.S.A. 98, 2278-2283.
  23. Lambeth, J. D. (2004) NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181-189.
  24. Landmesser, U., Cai, H., Dikalov, S., McCann, L., Hwang, J., Jo, H., Holland, S. M. and Harrison, D. G. (2002) Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40, 511-515.
  25. Landmesser, U., Dikalov, S., Price, S. R., McCann, L., Fukai, T., Holland, S. M., Mitch, W. E. and Harrison, D. G. (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Invest. 111, 1201-1209.
  26. Lassegue, B., Sorescu, D., Szocs, K., Yin, Q., Akers, M., Zhang, Y., Grant, S. L., Lambeth, J. D. and Griendling, K. K. (2001) Novel gp91(phox) homologues in vascular smooth muscle cells : nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ. Res. 88, 888-894.
  27. Laukkanen, M. O., Leppanen, P., Turunen, P., Pokkala-Sarataho, E., Salonen, J. T. and Yla-Herttulala, S. (2001) Gene transfer of extracellular superoxide dismutase to atherosclerotic mice. Antioxid. Redox Signal. 3, 397-402.
  28. Lee, M. Y., Martin, A. S., Mehta, P. K., Dikalova, A. E., Garrido, A. M., Datla, S. R., Lyons E., Krause, K., Banfi, B., Lambeth J. D., Lassegue, B. and Griendling K. K. (2009) Mechanism of vascular smooth muscle NADPH Oxidase 1 contribution to injury-induced neointimal formation. Arterioscler. Thromb. Vasc. Biol. 29, 480-487.
  29. Li, C., Hossieny, P., Wu, B. J., Qawasmeh, A., Beck, K. and Stocker, R. (2007) Pharmacologic induction of heme oxygenase-1. Antioxid. Redox Signal. 9, 2227-2239.
  30. Mayr, M., Chung, Y. L., Mayr, U., Yin, X., Ly, L., Troy, H., Fredericks, S., Hu, Y., Griffiths, J. R. and Xu, Q. (2005) Proteomic and metabolomic analyses of atherosclerotic vessels from apolipoprotein E-deficient mice reveal alterations in inflammation, oxidative stress, and energy metabolism. Arterioscler. Thromb. Vasc. Biol. 25, 2135-2142.
  31. McCord, J. M. (2004) Therapeutic control of free radicals. Drug Discov. Today 9, 781-782.
  32. Milenkovic, M., De Deken, X., Jin, L., De Felice, M., Di Lauro, R., Dumont, J. E., Corvilain, B. and Miot, F. (2007) Duox expression and related $H_2O_2$ measurement in mouse thyroid: onset in embryonic development and regulation by TSH in adult. J. Endocrinol. 192, 615-626.
  33. Musset, B., Clark, R. A., DeCoursey, T. E., Petheo, G. L., Geiszt, M., Chen, Y., Cornell, J. E., Eddy, C. A., Brzyski, R. G. and El Jamali, A. (2012) NOX5 in human spermatozoa expression, function, and regulation. J. Biol. Chem. 287, 9376-9388.
  34. Nguyen, V. D., Saaranen, M. J., Karala, A., Lappi, A., Wang, L., Raykhel, I. B., Alanen, H. I, Salo, K., Wang, C. and Ruddock, L. W. (2011) Two endoplasmic reticulum PDI peroxidases increase the efficiency of the use of peroxide during disulfide bind formation. J. Mol. Biol. 406, 503-515.
  35. Nishikawa, M., Hashida, M. and Takakura, Y. (2009) Catalase delivery for inhibiting ROS-mediated tissue injury and tumor metastasis. Adv. Drug Deliv. Rev. 61, 319-326.
  36. Nishikawa, M., Tamada, A., Kumai, H., Yamashita, F. and Hashida, M. (2002) Inhibition of experimental pulmonary metastasis by controlling biodistribution of catalase in mice. Int. J. Cancer 99, 474-479.
  37. Ohara, Y., Peterson, T. E. and Harrison, D. G. (1993) Hypercholesterolemia increases endothelial superoxide anion production. J. Clin. Invest. 91, 2546-2551.
  38. Olson, G. E., Whitin, J. C., Hill, K. E., Winfrey, V. P., Motley, A.K., Austin, L. M., Deal, J., Cohen, H. J. and Burk, R. F. (2010) Extracellular glutathione peroxidase(Gpx3) binds specifically to basement membranes of mouse renal cortex tubule cells. Am. J. Physiol. Renal Physiol. 298, F1244-1253.
  39. Park, J. G., Yoo, J. Y., Jeong, S. J., Choi, J. H., Lee, M. R., Lee, M. N., Hwa, L. J., Kim, H. C., Jo, H., Yu, D. Y., Kang, S. W., Rhee, S. G., Lee, M. H. and Oh, G. T. (2011) Peroxiredoxin 2 deficiency exacerbates atherosclerosis in apolipoprotein E-deficient mice. Circ. Res. 109, 739-749.
  40. Rajagopalan, S., Kurz, S., Munzel, T., Tarpey, M., Freeman, B. A., Griendling, K. K. and Harrison, D. G. (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J. Clin. Invest. 97, 1916-1923.
  41. Reddi, A. R., Jensen, L. T., Naranuntarat, A., Rosenfeld, L., Leung, E., Shah, R. and Culotta, V. C. (2009) The overlapping roles of manganese and Cu/Zn SOD in oxidative stress protection. Free Radic. Biol. Med. 46, 154-162.
  42. Rhee, S. G., Woo, H. A., Kil, I. S. and Bae, S. H. (2012) Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides. J. Biol. Chem. 287, 4403-4410.
  43. Ryter, S. W., Alam, J. and Choi, A. M. (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol. Rev. 86, 583-650.
  44. Safo, M. K., Musayev, F. N., Wu, S. H., Abraham, D. J. and Ko, T. P. (2001) Structure of tetragonal crystals of human erythrocyte catalase. Acta Crystallogr. D. Biol. Crystallogr. 57, 1-7.
  45. Sauer, H., Shah, A. M. and Laurindo, F. R. M. (2010) Studies on Cardiovascular Disorders, Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, New York.
  46. Sauer, H., Wartenberg, M. and Hescheler, J. (2001) Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell. Physiol. Biochem. 11, 173-186.
  47. Sentman, M. L., Brannstrom, T., Westerlund, S., Laukkanen, M. O., Yla-Herttuala, S., Basu, S. and Marklund, S. L. (2001) Extracellular superoxide dismutase deficiency and atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 21, 1477-1482.
  48. Sorescu, D., Weiss, D., Lassegue, B., Clempus, R. E., Szocs, K., Sorescu, G. P., Valppu, L., Quinn, M. T., Lambeth, J. D., Vega, J. D., Taylor, W. R. and Griendling, K. K. (2002) Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105, 1429-1435.
  49. Stocker, R. and Keaney, J. F. Jr. (2004) Role of oxidative modifications in atherosclerosis. Physiol. Rev. 84, 1381-1478.
  50. Suh, Y. A., Arnold, R. S., Lassegue, B., Shi, J., Xu, X., Sorescu, D., Chung, A. B., Griendling, K. K. and Lambeth, J. D. (1999) Cell transformation by the superoxide-generating oxidase Mox1. Nature 401, 79-82.
  51. Toppo, S., Flohe, L., Ursini, F., Vanin, S. and Maiorino, M. (2009) Catalytic mechanisms and specificities of glutathione peroxidases: variations of a basic scheme. Biochim. Biophys. Acta 1790, 1486-1500.
  52. Traber, M. G. and Atkinson, J. (2007) Vitamin E, antioxidant and nothing more. Free. Radic. Biol. Med. 43, 4-15.
  53. van Deel, E. D., Lu, Z., Xu, X., Zhu, G., Hu, X., Oury, T. D., Bache, R. J., Duncker, D. J., Chen, Y. (2008) Extracellular superoxide dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction. Free Radic. Biol. Med. 44, 1305-1313.
  54. van Empel. V. P., Bertrand, A. T., van Oort. R. J., van der, Nagel R., Engelen, M., van Rijen, H. V., Doevendans, P. A., Crijns, H. J., Ackerman, S. L., Sluiter, W. and De Windt, L. J. (2006) EUK-8, a superoxide dismutase and catalase mimetic, reduces cardiac oxidative stress and ameliorates pressure overload-induced heart failure in the harlequin mouse mutant. J. Am. Coll. Cardiol. 48, 824-832.
  55. Vernet, P., Rock, E., Mazur, A., Rayssiguier, Y., Dufaure, J. P. and Drevet, J. R. (1999) Selenium-independent epididymis-restricted glutathione peroxidase 5 protein (GPx5) can back up failing Se-dependent Gpxs in mice subjected to selenium deficiency. Mol. Reprod. Dev. 54, 362-370.<362::AID-MRD6>3.0.CO;2-#
  56. Watts, G. F. and Staels, B. (2004) Regulation of endothelial nitric oxide synthase by PPAR agonists: molecular and clinical perspectives. Arterioscler. Thromb. Vasc. Biol. 24, 619-621.
  57. Wei, Y., Liu, X. M., Peyton, K. J., Wang, H., Johnson, F. K., Johnson, R. A. and Durante, W. (2009) Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival. Am. J. Physiol. Cell Physiol. 297, C907-915.
  58. Wood, Z. A., Schroder, E., Robin Harris, J. and Poole, L. B. (2003) Structure, mechanism and regulation of peroxiredoxins. Trends. Biochem. Sci. 28, 32-40.
  59. Yan, W. and Chen, X. (2006) GPX2, a direct target of p63, inhibits oxidative stress-induced apoptosis in a p53-dependent manner. J. Biol. Chem. 281, 7856-7862.
  60. Yang, H., Roberts, L. J., Shi, M. J., Zhou, L. C., Ballard, B. R., Richardson, A. and Guo, Z. M. (2004) Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E. Circ. Res. 95, 1075-1081.
  61. Zhang, F., Strom, A., Fukada, K., Lee, S., Hayward, L. J. and Zhu, H. (2007) Interaction between Familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 Mutants and the Dynein Complex. J. Biol. Chem. 282, 16691-16699.

Cited by

  1. Characteristics of Skeletal Muscle Fibers of SOD1 Knockout Mice vol.2016, 2016,
  2. Novel carters and targeted approaches: Way out for rheumatoid arthritis quandrum vol.40, 2017,
  3. Anti-inflammatory activity of AP-SF, a ginsenoside-enriched fraction, from Korean ginseng vol.39, pp.2, 2015,
  4. Skeletal Muscle TRIB3 Mediates Glucose Toxicity in Diabetes and High- Fat Diet–Induced Insulin Resistance vol.65, pp.8, 2016,
  5. The protective effects of trace elements against side effects induced by ionizing radiation vol.33, pp.2, 2015,
  6. Novel anti-inflammatory function of NSC95397 by the suppression of multiple kinases vol.88, pp.2, 2014,
  7. Syk/Src-targeted anti-inflammatory activity of Codariocalyx motorius ethanolic extract vol.155, pp.1, 2014,
  8. ATF-2/CREB/IRF-3-targeted anti-inflammatory activity of Korean red ginseng water extract vol.154, pp.1, 2014,
  9. 21-O-Angeloyltheasapogenol E3, a Novel Triterpenoid Saponin from the Seeds of Tea Plants, Inhibits Macrophage-Mediated Inflammatory Responses in a NF-κB-Dependent Manner vol.2014, 2014,
  10. Cornelian cherry consumption increases the l -arginine/ADMA ratio, lowers ADMA and SDMA levels in the plasma, and enhances the aorta glutathione level in rabbits fed a high-cholesterol diet vol.34, 2017,
  11. Translational and post-translational regulation of mouse cation transport regulator homolog 1 vol.6, pp.1, 2016,
  12. Molecular mechanism of protopanaxadiol saponin fraction-mediated anti-inflammatory actions vol.39, pp.1, 2015,
  13. Impact of eNOS-Dependent Oxidative Stress on Endothelial Function and Neointima Formation vol.23, pp.9, 2015,
  14. Cytoprotective and Cytotoxic Effects of Rice Bran Extracts in Rat H9c2(2-1) Cardiomyocytes vol.2016, 2016,
  15. 1,8-Cineole ameliorates oxygen-glucose deprivation/reoxygenation-induced ischaemic injury by reducing oxidative stress in rat cortical neuron/glia vol.66, pp.12, 2014,
  16. AKT-targeted anti-inflammatory activity of Panax ginseng calyx ethanolic extract 2017,
  17. 6-Gingerol Attenuates Hydrogen Peroxide-induced DNA Damage in Human Umbilical Vein Endothelia Cells vol.20, pp.5, 2014,
  18. (5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl 6-hydroxynaphthalene-2-carboxylate, a kojic acid derivative, inhibits inflammatory mediator production via the suppression of Syk/Src and NF-κB activation vol.20, pp.1, 2014,
  19. Chlamydia pneumoniae and Oxidative Stress in Cardiovascular Disease: State of the Art and Prevention Strategies vol.16, pp.1, 2014,
  20. Cytoprotective Activity and Anti-inflammatory Properties of Artemisia nilagirica (Clarke) Extracts-A Study with Macrophages vol.7, pp.3, 2017,
  21. Involvement of the Antioxidant Effect and Anti-inflammatory Response in Butyrate-Inhibited Vascular Smooth Muscle Cell Proliferation vol.7, pp.11, 2014,
  22. Lancemaside A fromCodonopsis lanceolataModulates the Inflammatory Responses Mediated by Monocytes and Macrophages vol.2014, 2014,
  23. Reactive oxygen species regulate the quiescence of CD34-positive cells derived from human embryonic stem cells vol.103, pp.1, 2014,
  24. ROS-mediated carbon monoxide and drug release from drug-conjugated carboxyboranes vol.47, pp.2, 2018,
  25. Influence of bradykinin B2 receptor and dopamine D2 receptor on the oxidative stress, inflammatory response, and apoptotic process in human endothelial cells vol.13, pp.11, 2018,