The Paradigm of Oxidative Stress Reduction Oxidation Concepts

Reactive oxygen species are formed as intermediates in reduction-oxidation (redox) processes, leading from oxygen to water. The fundamental mechanism underlying redox processes in chemico-biologic interactions is that of addition of an oxygen molecule (oxidation) to form an oxidant or removal of oxygen (reduction) to form a reductant24-26 (Fig. 4.1). Alternative approaches to describe oxidation and reduction are the loss of electrons (or hydrogen) and the gaining of electrons (or hydrogen), respectively.25 The univalent reduction of oxygen, in the presence of a free electron (e-), yields »O2-, H2O2 and »OH (Fig. 4.2). Superoxide has an unpaired electron, which imparts high reactivity and renders it unstable and short lived. Superoxide is water soluble and acts either as an oxidizing agent, where it is reduced to H2O2, or as a reducing agent, where it donates its extra electron to form ONOO- with NO.27 Under

Redox Reactions

Redox Reactions

physiological conditions in aqueous solutions at a neutral pH, its preferred reaction is the dismutation reaction yielding H2O2. However, when produced in excess, a significant amount of »O2- reacts with NO to produce ONOO-.27 Superoxide is membrane-impermeable, but can cross cell membranes via anion channels.28,29 Hydrogen peroxide is produced primarily from dismutation of »O2-. This reaction can be spontaneous or it can be catalyzed by superoxide dismutase.24 The SOD-catalyzed dismutation is favored when the concentration of »O2- is low and when the concentration of SOD is high, which occurs normally. Hydrogen peroxide is lipid soluble, crosses cell membranes, and is stable under physiological conditions. In biologic systems, it is scavenged by catalase and by glutathione peroxidase.30 Hydrogen peroxide can also be reduced to generate the highly reactive »OH (Haber-Weiss or Fenton reaction) in the presence of iron-containing molecules such as Fe2+. Hydroxyl radical is extremely reactive and unlike »O2- and H2O2, which travel some distance from their site of generation, »OH induces local damage where it is formed.

Humans consume «250 g of oxygen per day, and of this 3-5% is converted to »O2- and other ROS.31 A typical human cell metabolizes about 1012 molecules of O2 daily and generates approximately 3x109 molecules of H2O2 per hour. Superoxide anion, H2O2 NO, OONO-, and »OH are all produced to varying degrees in the vasculature. These pro-oxidants, which are tightly regulated by antioxidants under normal conditions, act as second messengers to control vascular function and structure. An imbalance between oxidant production and antioxidant defenses results in oxidative stress and consequent cell damage.25,30



Glutathione peroxidase


Xanthine oxidase


Mitochondrial respiration




Cytochrome P450


Fig. 4.2 Regulation of reactive oxygen species (ROS) production in vascular smooth muscle cells. The major source of vascular 'O2-is cell-membrane-associated non-phagocytic NAD(P)H oxidase. NAD(P)H oxidase is a multi-subunit enzyme comprising gp91phox (Nox2)/Nox1/Nox4, p22phox, p47phox, p67phox and p40phox. Many other enzyme systems, including uncoupled nitric oxide synthase (NOS), also produce 'O2- but their role is minor in vascular cells in hypertension. Extracellular stimuli, such as Ang II, activate NAD(P)H oxidase activity. H2O2 but not 'O2-is lipid soluble and can freely cross the cell membrane SOD, superoxide dismutase; e-, electron, BH2, dihydrobiopterin

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