Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 338–349 (2008)Cite this article

Abstract

Endothelial cells control vascular homeostasis by generating paracrine factors that regulate vascular tone, inhibit platelet function, prevent adhesion of leukocytes, and limit proliferation of vascular smooth muscle. The dominant factor responsible for many of those effects is endothelium-derived nitric oxide (NO). Endothelial dysfunction characterized by enhanced inactivation or reduced synthesis of NO, alone or in combination, is seen in conjunction with risk factors for cardiovascular disease. Endothelial dysfunction can promote vasospasm, thrombosis, vascular inflammation, and proliferation of the intima. Vascular oxidative stress and increased production of reactive oxygen species contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase or the mitochondrial respiratory chain) and antioxidant enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase and paraoxonase). In addition, small-molecular-weight antioxidants might have a role in the defense against oxidative stress. Increased concentrations of reactive oxygen species reduce bioactive NO through chemical inactivation, forming toxic peroxynitrite, which in turn can uncouple endothelial NO synthase to form a dysfunctional superoxide-generating enzyme that contributes further to oxidative stress. The role of oxidative stress in vascular dysfunction and atherogenesis, and strategies for its prevention are discussed.

Key Points

  • Oxidative stress in the vasculature is associated with most, if not all, cardiovascular risk factors such as hypertension, diabetes mellitus, hypercholesterolemia and smoking, and experimental and clinical evidence indicates that vascular oxidative stress predisposes a patient to the development of atherosclerosis

  • During oxidative stress, enzyme systems that produce reactive oxygen species are activated and prevail over those that protect against oxidative stress, leading to a significant reduction of bioactive nitric oxide (NO) in the vasculature through rapid oxidation of NO itself and through 'uncoupling' of endothelial NO synthase

  • As a result of these processes, the various protective effects of NO are lost and multiple proinflammatory and proatherosclerotic pathways and gene products are activated and expressed—the major molecular basis of endothelial dysfunction

  • Currently, no evidence supports vitamin C supplementation for reducing the risk of cardiovascular morbidity or mortality, and the use of vitamin E in primary prevention of cardiovascular disease is discouraged

  • Epidemiological evidence indicates that consumption of polyphenol-rich foods and beverages reduces the incidence of cardiovascular disease

  • Of the existing drug classes used to treat cardiovascular disease, angiotensin-converting-enzyme inhibitors, angiotensin II receptor antagonists and statins have been shown to reduce vascular oxidative stress, improve endothelial function and provide a prognostic benefit

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Enzyme systems involved in the generation and inactivation of reactive oxygen species.
Figure 2: Endothelial nitric oxide synthase.
Figure 3: Inducible heme oxygenase 1 and its products function as adaptive molecules against oxidative stress.
Figure 4: Endothelial dysfunction in human coronary arteries and atherosclerotic disease progression.
Figure 5: Vascular oxidative stress as a cause of atherogenesis.

Similar content being viewed by others

References

  1. Förstermann U and Münzel T (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113: 1708–1714

    Article  PubMed  CAS  Google Scholar 

  2. Li H et al. (2006) Reversal of eNOS uncoupling and upregulation of eNOS expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol 47: 2536–2544

    Article  CAS  PubMed  Google Scholar 

  3. Hink U et al. (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88: E14–E22

    Article  CAS  PubMed  Google Scholar 

  4. Warnholtz A et al. (1999) Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 99: 2027–2033

    Article  CAS  PubMed  Google Scholar 

  5. Sorescu D et al. (2002) Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105: 1429–1435

    Article  CAS  PubMed  Google Scholar 

  6. Mueller CF et al. (2005) ATVB in focus: redox mechanisms in blood vessels. Arterioscler Thromb Vasc Biol 25: 274–278

    Article  CAS  PubMed  Google Scholar 

  7. Griendling KK (2004) Novel NAD(P)H oxidases in the cardiovascular system. Heart 90: 491–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fukui T et al. (1997) p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ Res 80: 45–51

    Article  CAS  PubMed  Google Scholar 

  9. Matsuno K et al. (2005) Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation 112: 2677–2685

    Article  CAS  PubMed  Google Scholar 

  10. Landmesser U et al. (2002) Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40: 511–515

    Article  CAS  PubMed  Google Scholar 

  11. Barry-Lane PA et al. (2001) p47phox is required for atherosclerotic lesion progression in ApoE(-/-) mice. J Clin Invest 108: 1513–1522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dikalova A et al. (2005) Nox1 overexpression potentiates angiotensin II-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice. Circulation 112: 2668–2676

    Article  CAS  PubMed  Google Scholar 

  13. Ohara Y et al. (1993) Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 91: 2546–2551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. White CR et al. (1996) Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits. Proc Natl Acad Sci USA 93: 8745–8749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McNally JS et al. (2003) 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 285: H2290–H2297

    Article  CAS  PubMed  Google Scholar 

  16. Butler R et al. (2000) Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 35: 746–751

    Article  CAS  PubMed  Google Scholar 

  17. O'Driscoll JG et al. (1999) Nitric oxide-dependent endothelial function is unaffected by allopurinol in hypercholesterolaemic subjects. Clin Exp Pharmacol Physiol 26: 779–783

    Article  CAS  PubMed  Google Scholar 

  18. Turrens JF et al. (1985) Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys 237: 408–414

    Article  CAS  PubMed  Google Scholar 

  19. Ramachandran A et al. (2002) Mitochondria, nitric oxide, and cardiovascular dysfunction. Free Radic Biol Med 33: 1465–1474

    Article  CAS  PubMed  Google Scholar 

  20. Ballinger SW et al. (2002) Mitochondrial integrity and function in atherogenesis. Circulation 106: 544–549

    Article  CAS  PubMed  Google Scholar 

  21. Ohashi M et al. (2006) MnSOD deficiency increases endothelial dysfunction in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 26: 2331–2336

    Article  CAS  PubMed  Google Scholar 

  22. Stroes E et al. (1997) Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 99: 41–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Heitzer T et al. (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia 43: 1435–1438

    Article  CAS  PubMed  Google Scholar 

  24. Higashi Y et al. (2002) Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in both normotensive and hypertensive individuals. Am J Hypertens 15: 326–332

    Article  CAS  PubMed  Google Scholar 

  25. Martasek P et al. (1998) The C331A mutant of neuronal nitric-oxide synthase is defective in arginine binding. J Biol Chem 273: 34799–34805

    Article  CAS  PubMed  Google Scholar 

  26. Werner ER et al. (2003) Tetrahydrobiopterin and nitric oxide: mechanistic and pharmacological aspects. Exp Biol Med (Maywood) 228: 1291–1302

    Article  CAS  Google Scholar 

  27. Landmesser U et al. (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111: 1201–1209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mollnau H et al. (2002) Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90: E58–E65

    Article  PubMed  Google Scholar 

  29. Jung O et al. (2007) Inactivation of extracellular superoxide dismutase contributes to the development of high-volume hypertension. Arterioscler Thromb Vasc Biol 27: 470–477

    Article  CAS  PubMed  Google Scholar 

  30. Yoshida K et al. (1993) Nitric oxide synthase-immunoreactive nerve fibers in dog cerebral and peripheral arteries. Brain Res 629: 67–72

    Article  CAS  PubMed  Google Scholar 

  31. Iida S et al. (2006) Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure. Am J Physiol Heart Circ Physiol 291: H914–H920

    Article  CAS  PubMed  Google Scholar 

  32. Yoshida T et al. (1997) Glutathione peroxidase knockout mice are susceptible to myocardial ischemia reperfusion injury. Circulation 96 (Suppl 9): II-216-220

    Google Scholar 

  33. Blankenberg S et al.; AtheroGene Investigators (2003) Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N Engl J Med 349: 1605–1613

    Article  CAS  PubMed  Google Scholar 

  34. Torzewski M et al. (2007) Deficiency of glutathione peroxidase-1 accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 27: 850–857

    Article  CAS  PubMed  Google Scholar 

  35. Imai H et al. (2003) Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochem Biophys Res Commun 305: 278–286

    Article  CAS  PubMed  Google Scholar 

  36. Ho YS et al. (2004) Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. J Biol Chem 279: 32804–32812

    Article  CAS  PubMed  Google Scholar 

  37. Zhang Y et al. (2005) Vascular hypertrophy in angiotensin II-induced hypertension is mediated by vascular smooth muscle cell-derived H2O2. Hypertension 46: 732–737

    Article  CAS  PubMed  Google Scholar 

  38. Yang H et al. (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

    Article  CAS  PubMed  Google Scholar 

  39. Stocker R and Perrella MA (2006) Heme oxygenase-1: a novel drug target for atherosclerotic diseases. Circulation 114: 2178–2189

    Article  CAS  PubMed  Google Scholar 

  40. Jiang F et al. (2006) NO modulates NADPH oxidase function via heme oxygenase-1 in human endothelial cells. Hypertension 48: 950–957

    Article  CAS  PubMed  Google Scholar 

  41. Taille C et al. (2004) Induction of heme oxygenase-1 inhibits NAD(P)H oxidase activity by down-regulating cytochrome b558 expression via the reduction of heme availability. J Biol Chem 279: 28681–28688

    Article  CAS  PubMed  Google Scholar 

  42. Morita T (2005) Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 25: 1786–1795

    Article  CAS  PubMed  Google Scholar 

  43. Hoekstra KA et al. (2004) Protective role of heme oxygenase in the blood vessel wall during atherogenesis. Biochem Cell Biol 82: 351–359

    Article  CAS  PubMed  Google Scholar 

  44. Yamawaki H et al. (2003) Thioredoxin: a key regulator of cardiovascular homeostasis. Circ Res 93: 1029–1033

    Article  CAS  PubMed  Google Scholar 

  45. Aviram M et al. (1998) Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest 101: 1581–1590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rozenberg O et al. (2005) Paraoxonase 1 (PON1) attenuates macrophage oxidative status: studies in PON1 transfected cells and in PON1 transgenic mice. Atherosclerosis 181: 9–18

    Article  CAS  PubMed  Google Scholar 

  47. Tward A et al. (2002) Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation 106: 484–490

    Article  CAS  PubMed  Google Scholar 

  48. Leus FR et al. (2001) PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients. Atherosclerosis 154: 641–649

    Article  CAS  PubMed  Google Scholar 

  49. Horke S et al. (2007) Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation. Circulation 115: 2055–2064

    Article  CAS  PubMed  Google Scholar 

  50. Ng CJ et al. (2006) Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2. J Biol Chem 281: 29491–29500

    Article  CAS  PubMed  Google Scholar 

  51. May JM (2000) How does ascorbic acid prevent endothelial dysfunction. Free Radic Biol Med 28: 1421–1429

    Article  CAS  PubMed  Google Scholar 

  52. Heller R et al. (2001) L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 276: 40–47

    Article  CAS  PubMed  Google Scholar 

  53. Wallerath T et al. (2002) Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 106: 1652–1658

    Article  CAS  PubMed  Google Scholar 

  54. Wallerath T et al. (2005) A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide 12: 97–104

    Article  CAS  PubMed  Google Scholar 

  55. Vita JA et al. (1990) Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 81: 491–497

    Article  CAS  PubMed  Google Scholar 

  56. Nickenig G and Harrison DG (2002) The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I—oxidative stress and atherogenesis. Circulation 105: 393–396

    Article  CAS  PubMed  Google Scholar 

  57. Zalba G et al. (2001) Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 38: 1395–1399

    Article  CAS  PubMed  Google Scholar 

  58. Wassmann S et al. (2001) 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 59: 646–654

    Article  CAS  PubMed  Google Scholar 

  59. Touyz RM et al. (2003) c-Src induces phosphorylation and translocation of p47phox: role in superoxide generation by angiotensin II in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 23: 981–987

    Article  CAS  PubMed  Google Scholar 

  60. Grote K et al. (2003) Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase-derived reactive oxygen species. Circ Res 92: e80–e86

    Article  CAS  PubMed  Google Scholar 

  61. Wassmann S et al. (2001) HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 37: 1450–1457

    Article  CAS  PubMed  Google Scholar 

  62. Schächinger V et al. (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101: 1899–1906

    Article  PubMed  Google Scholar 

  63. Heitzer T et al. (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104: 2673–2678

    Article  CAS  PubMed  Google Scholar 

  64. Stocker R and Keaney JF Jr (2005) New insights on oxidative stress in the artery wall. J Thromb Haemost 3: 1825–1834

    Article  CAS  PubMed  Google Scholar 

  65. Kunsch C and Medford RM (1999) Oxidative stress as a regulator of gene expression in the vasculature. Circ Res 85: 753–766

    Article  CAS  PubMed  Google Scholar 

  66. Viedt C et al. (2000) Differential activation of mitogen-activated protein kinases in smooth muscle cells by angiotensin II: involvement of p22phox and reactive oxygen species. Arterioscler Thromb Vasc Biol 20: 940–948

    Article  CAS  PubMed  Google Scholar 

  67. Tonks NK (2005) Redox redux: revisiting PTPs and the control of cell signaling. Cell 121: 667–670

    Article  CAS  PubMed  Google Scholar 

  68. Landmesser U et al. (2000) Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 101: 2264–2270

    Article  CAS  PubMed  Google Scholar 

  69. Gokce N et al. (1999) Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 99: 3234–3240

    Article  CAS  PubMed  Google Scholar 

  70. Ellis GR et al. (2000) Neutrophil superoxide anion—generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy. J Am Coll Cardiol 36: 1474–1482

    Article  CAS  PubMed  Google Scholar 

  71. Paolini M et al. (2003) Antioxidant vitamins for prevention of cardiovascular disease. Lancet 362: 920

    Article  PubMed  Google Scholar 

  72. Stanner SA et al. (2004) A review of the epidemiological evidence for the 'antioxidant hypothesis'. Public Health Nutr 7: 407–422

    Article  CAS  PubMed  Google Scholar 

  73. Lonn E et al.; HOPE and HOPE-TOO Trial Investigators (2005) Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293: 1338–1347

    Article  PubMed  Google Scholar 

  74. Klingbeil AU et al. (2003) Effect of AT1 receptor blockade on endothelial function in essential hypertension. Am J Hypertens 16: 123–128

    Article  CAS  PubMed  Google Scholar 

  75. Hornig B et al. (2001) Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation 103: 799–805

    Article  CAS  PubMed  Google Scholar 

  76. Takase H et al. (2000) Long-term effect of antihypertensive therapy with calcium antagonist or angiotensin converting enzyme inhibitor on serum nitrite/nitrate levels in human essential hypertension. Arzneimittelforschung 50: 530–534

    CAS  PubMed  Google Scholar 

  77. Yusuf S et al. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342: 145–153

    Article  CAS  PubMed  Google Scholar 

  78. Fox KM ; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators (2003) Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 362: 782–788

    Article  CAS  PubMed  Google Scholar 

  79. Braunwald E et al.; PEACE Trial Investigators (2004) Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 351: 2058–2068

    Article  CAS  PubMed  Google Scholar 

  80. Liao JK (2002) Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol 86: 5–18

    Article  PubMed  Google Scholar 

  81. Wagner AH et al. (2000) Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 20: 61–69

    Article  CAS  PubMed  Google Scholar 

  82. Landmesser U et al. (2005) Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 111: 2356–2363

    Article  CAS  PubMed  Google Scholar 

  83. Laufs U and Liao JK (1998) Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 273: 24266–24271

    Article  CAS  PubMed  Google Scholar 

  84. Kureishi Y et al. (2000) The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6: 1004–1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Straße 67, 55101 Mainz, Germany ulrich.forstermann@uni-mainz.de

Authors and Affiliations

  1. U Förstermann is Professor and Chairman of the Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.,

    Ulrich Förstermann

Authors
  1. Ulrich Förstermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Förstermann, U. Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Rev Cardiol 5, 338–349 (2008). https://doi.org/10.1038/ncpcardio1211

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio1211

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing