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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

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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.

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

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

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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

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