Current Hypertension Reports

, Volume 8, Issue 1, pp 69–78

Regulation of antioxidant and oxidant enzymes in vascular cells and implications for vascular disease



Data from numerous studies demonstrate that oxidative stress plays an important role in the pathogenesis of vascular disease. Oxidative stress leads to many pathologic events, such as inactivation of nitric oxide, lipid oxidation, enhanced mitogenicity and apoptosis of vascular cells, and increased expression and activation of redox-sensitive genes, which contribute to atherogenesis at all stages of the disease. Multiple enzymes are expressed in vascular cells that are involved in the elimination and production of reactive oxygen species, including the superoxide dismutases, catalase, thioredoxin reductase, glutathione peroxidase, NAD(P)H oxidase, xanthine oxidase, myeloperoxidase, and endothelial nitric oxide synthase. Several agonists and pathologic conditions that predispose to vascular disease induce changes in the expression and activity levels of these antioxidant and oxidant enzyme systems, leading to modulation of vascular oxygen radical load. Identification of key enzymes and mechanisms of vascular oxidative stress is important for the development of novel, specific pharmacologic interventions.


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References and Recommended Reading

  1. 1.
    McNally JS, Davis ME, Giddens DP, et al.: Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol Heart Circ Physiol 2003, 285:H2290-H2297.PubMedGoogle Scholar
  2. 2.
    Drummond GR, Cai H, Davis ME, et al.: Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ Res 2000, 86:347–354.PubMedGoogle Scholar
  3. 3.
    Li WG, Miller FJ Jr, Zhang HJ, et al.: H(2)O(2)-induced O(2) production by a non-phagocytic NAD(P)H oxidase causes oxidant injury. J Biol Chem 2001, 276:29251–29256.PubMedCrossRefGoogle Scholar
  4. 4.
    Meilhac O, Zhou M, Santanam N, Parthasarathy S: Lipid peroxides induce expression of catalase in cultured vascular cells. J Lipid Res 2000, 41:1205–1213.PubMedGoogle Scholar
  5. 5.
    Fukai T, Siegfried MR, Ushio-Fukai M, et al.: Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest 2000, 105:1631–1639.PubMedGoogle Scholar
  6. 6.
    Landmesser U, Dikalov S, Price SR, et al.: Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 2003, 111:1201–1209. This study demonstrates eNOS uncoupling as a source of oxidative stress in experimental hypertension.PubMedCrossRefGoogle Scholar
  7. 7.
    Mollnau H, Wendt M, Szocs K, et al.: Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 2002, 90:E58-E65. This animal study shows mechanisms of oxidative stress in angiotensin II-mediated hypertension.PubMedCrossRefGoogle Scholar
  8. 8.
    Park YS, Fujiwara N, Koh YH, et al.: Induction of thioredoxin reductase gene expression by peroxynitrite in human umbilical vein endothelial cells. Biol Chem 2002, 383:683–691.PubMedCrossRefGoogle Scholar
  9. 9.
    Lassegue B, Clempus RE: Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 2003, 285:R277-R297. This extensive review describes in detail the function and regulation of vascular NAD(P)H oxidase.PubMedGoogle Scholar
  10. 10.
    Stralin P, Marklund SL: Multiple cytokines regulate the expression of extracellular superoxide dismutase in human vascular smooth muscle cells. Atherosclerosis 2000, 151:433–441.PubMedCrossRefGoogle Scholar
  11. 11.
    Brandes RP, Koddenberg G, Gwinner W, et al.: Role of increased production of superoxide anions by NAD(P)H oxidase and xanthine oxidase in prolonged endotoxemia. Hypertension 1999, 33:1243–1249.PubMedGoogle Scholar
  12. 12.
    Stralin P, Marklund SL: Vasoactive factors and growth factors alter vascular smooth muscle cell ec-SOD expression. Am J Physiol Heart Circ Physiol 2001, 281:H1621-H1629.PubMedGoogle Scholar
  13. 13.
    Laufs U, Adam O, Strehlow K, et al.: Downregulation of rac-1 GTPase by estrogen. J Biol Chem 2003, 278:5956–5962.PubMedCrossRefGoogle Scholar
  14. 14.
    Seshiah PN, Weber DS, Rocic P, et al.: Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res 2002, 91:406–413.PubMedCrossRefGoogle Scholar
  15. 15.
    Wassmann S, Laufs U, Baumer AT, et al.: Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 2001, 59:646–654.PubMedGoogle Scholar
  16. 16.
    Mervaala EM, Cheng ZJ, Tikkanen I, et al.: Endothelial dysfunction and xanthine oxidoreductase activity in rats with human renin and angiotensinogen genes. Hypertension 2001, 37:414–418.PubMedGoogle Scholar
  17. 17.
    Fukai T, Siegfried MR, Ushio-Fukai M, et al.: Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. Circ Res 1999, 85:23–28.PubMedGoogle Scholar
  18. 18.
    Nickenig G, Harrison DG: The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: Part II: AT(1) receptor regulation. Circulation 2002, 105:530–536.PubMedCrossRefGoogle Scholar
  19. 19.
    Landmesser U, Cai H, Dikalov S, et al.: Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 2002, 40:511–515.PubMedCrossRefGoogle Scholar
  20. 20.
    Heitzer T, Wenzel U, Hink U, et al.: Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase C. Kidney Int 1999, 55:252–260.PubMedCrossRefGoogle Scholar
  21. 21.
    Cosentino F, Patton S, d’Uscio LV, et al.: Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats. J Clin Invest 1998, 101:1530–1537.PubMedCrossRefGoogle Scholar
  22. 22.
    Zalba G, Beaumont FJ, San Jose G, et al.: Vascular NADH/ NADPH oxidase is involved in enhanced superoxide production in spontaneously hypertensive rats. Hypertension 2000, 35:1055–1061.PubMedGoogle Scholar
  23. 23.
    Zalba G, San Jose G, Moreno MU, et al.: Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 2001, 38:1395–1399.PubMedGoogle Scholar
  24. 24.
    Wassmann S, Czech T, van EickelsM, et al.: Inhibition of diet-induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A receptor double-knockout mice. Circulation 2004, 110:3062–3067. This animal study shows the importance of AT1 receptor activation and accompanying oxidative stress for atherogenesis using a genetic approach.PubMedCrossRefGoogle Scholar
  25. 25.
    Inoguchi T, Li P, Umeda F, et al.: High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C—dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000, 49:1939–1945.PubMedCrossRefGoogle Scholar
  26. 26.
    Hink U, Li H, Mollnau H, et al.: Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 2001, 88:E14-E22. This study demonstrates mechanisms of oxidative stress in experimental type 1 diabetes mellitus.PubMedGoogle Scholar
  27. 27.
    Matsumoto S, Koshiishi I, Inoguchi T, et al.: Confirmation of superoxide generation via xanthine oxidase in streptozotocin-induced diabetic mice. Free Radic Res 2003, 37:767–772.PubMedCrossRefGoogle Scholar
  28. 28.
    Guzik TJ, Mussa S, Gastaldi D, et al.: Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 2002, 105:1656–1662.PubMedCrossRefGoogle Scholar
  29. 29.
    Kim YK, Lee MS, Son SM, et al.: Vascular NADH oxidase is involved in impaired endothelium-dependent vasodilation in OLETF rats, a model of type 2 diabetes. Diabetes 2002, 51:522–527.PubMedCrossRefGoogle Scholar
  30. 30.
    Wagner AH, Schroeter MR, Hecker M: 17-beta-estradiol inhibition of NADPH oxidase expression in human endothelial cells. FASEB J 2001, 15:2121–2130.PubMedCrossRefGoogle Scholar
  31. 31.
    Wassmann S, Laufs U, Stamenkovic D, et al.: Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production. Circulation 2002, 105:2083–2091.PubMedCrossRefGoogle Scholar
  32. 32.
    Ejima K, Nanri H, Araki M, et al.: 17-beta-estradiol induces protein thiol/disulfide oxidoreductases and protects cultured bovine aortic endothelial cells from oxidative stress. Eur J Endocrinol 1999, 140:608–613.PubMedCrossRefGoogle Scholar
  33. 33.
    Strehlow K, Rotter S, Wassmann S, et al.: Modulation of antioxidant enzyme expression and function by estrogen. Circ Res 2003, 93:170–177.PubMedCrossRefGoogle Scholar
  34. 34.
    Wassmann K, Wassmann S, Nickenig G: Progesterone antagonizes the vasoprotective effect of estrogen on antioxidant enzyme expression and function. Circ Res 2005, 97:1046–1054.PubMedCrossRefGoogle Scholar
  35. 35.
    Laufs U, Wassmann S, Czech T, et al.: Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arterioscler Thromb Vasc Biol 2005, 25:809–814.PubMedCrossRefGoogle Scholar
  36. 36.
    Rush JW, Turk JR, Laughlin MH: Exercise training regulates SOD-1 and oxidative stress in porcine aortic endothelium. Am J Physiol Heart Circ Physiol 2003, 284:H1378-H1387.PubMedGoogle Scholar
  37. 37.
    Adams V, Linke A, Krankel N, et al.: Impact of regular physical activity on the NAD(P)H oxidase and angiotensin receptor system in patients with coronary artery disease. Circulation 2005, 111:555–562. This human study evaluated the effect of physical exercise on vascular oxidative stress and endothelial function in patients with coronary artery disease.PubMedCrossRefGoogle Scholar
  38. 38.
    Warnholtz A, Nickenig G, Schulz E, et al.: Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 1999, 99:2027–2033.PubMedGoogle Scholar
  39. 39.
    Koh KK, Ahn JY, Han SH, et al.: Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. J Am Coll Cardiol 2003, 42:905–910.PubMedCrossRefGoogle Scholar
  40. 40.
    Wassmann S, Hilgers S, Laufs U, et al.: Angiotensin II type 1 receptor antagonism improves hypercholesterolemiaassociated endothelial dysfunction. Arterioscler Thromb Vasc Biol 2002, 22:1208–1212.PubMedCrossRefGoogle Scholar
  41. 41.
    Berkels R, Egink G, Marsen TA, et al.: Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms. Hypertension 2001, 37:240–245.PubMedGoogle Scholar
  42. 42.
    Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, et al.: Third-generation beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation 2003, 107:2747–2752.PubMedCrossRefGoogle Scholar
  43. 43.
    Calnek DS, Mazzella L, Roser S, et al.: Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 2003, 23:52–57.PubMedCrossRefGoogle Scholar
  44. 44.
    Inoue I, Goto S, Matsunaga T, et al.: The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism 2001, 50:3–11.PubMedCrossRefGoogle Scholar
  45. 45.
    Diep QN, Amiri F, Touyz RM, et al.: PPARalpha activator effects on Ang II-induced vascular oxidative stress and inflammation. Hypertension 2002, 40:866–871.PubMedCrossRefGoogle Scholar
  46. 46.
    Desco MC, Asensi M, Marquez R, et al.: Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. Diabetes 2002, 51:1118–1124.PubMedCrossRefGoogle Scholar
  47. 47.
    Doehner W, Schoene N, Rauchhaus M, et al.: Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 2002, 105:2619–2624.PubMedCrossRefGoogle Scholar
  48. 48.
    Laufs U, La Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998, 97:1129–1135.PubMedGoogle Scholar
  49. 49.
    Wassmann S, Laufs U, Muller K, et al.: Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 2002, 22:300–305.PubMedCrossRefGoogle Scholar
  50. 50.
    Sorescu D, Weiss D, Lassegue B, et al.: Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 2002, 105:1429–1435. This study demonstrates enhanced ROS production and NAD(P)H oxidase expression in human atherosclerotic plaques.PubMedCrossRefGoogle Scholar
  51. 51.
    Spiekermann S, Landmesser U, Dikalov S, et al.: Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 2003, 107:1383–1389.PubMedCrossRefGoogle Scholar
  52. 52.
    Szocs K, Lassegue B, Sorescu D, et al.: Upregulation of Nox-based NAD(P)H oxidases in restenosis after carotid injury. Arterioscler Thromb Vasc Biol 2002, 22:21–27.PubMedCrossRefGoogle Scholar
  53. 53.
    Barry-Lane PA, Patterson C, van der MerweM, et al.: p47phox is required for atherosclerotic lesion progression in ApoE(-/-) mice. J Clin Invest 2001, 108:1513–1522. This experimental genetic study shows the importance of NAD(P)H oxidase-mediated oxidative stress for atherogenesis.PubMedCrossRefGoogle Scholar
  54. 54.
    Landmesser U, Merten R, Spiekermann S, et al.: Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: relation to endotheliumdependent vasodilation. Circulation 2000, 101:2264–2270. This human study demonstrated reduced ecSOD activity in patients with coronary artery disease.PubMedGoogle Scholar
  55. 55.
    Blankenberg S, Rupprecht HJ, Bickel C, et al.: Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N Engl J Med 2003, 349:1605–1613. This study shows the prognostic value of reduced GPX activity as an oxidative stress marker in patients with coronary artery disease.PubMedCrossRefGoogle Scholar
  56. 56.
    Brennan ML, Penn MS, Van LenteF, et al.: Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003, 349:1595–1604. This study shows the prognostic value of myeloperoxidase as an oxidative stress marker in patients with chest pain.PubMedCrossRefGoogle Scholar
  57. 57.
    Schwedhelm E, Bartling A, Lenzen H, et al.: Urinary 8-isoprostaglandin F2alpha as a risk marker in patients with coronary heart disease: a matched case-control study. Circulation 2004, 109:843–848.PubMedCrossRefGoogle Scholar
  58. 58.
    Yusuf S, Dagenais G, Pogue J, et al.: Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000, 342:154–160.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2006

Authors and Affiliations

  1. 1.Medizinische Klinik IIUniversitätsklinikum BonnBonnGermany

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