Review articleExtracellular superoxide dismutase in biology and medicine
Introduction
With the evolution of aerobic respiration within microbial organisms and the consequential formation of reactive oxygen species (ROS) came the need for antioxidant enzymes to counteract the deleterious effects of these oxygen metabolites. Low levels of ROS are vital for many cell signaling events and are essential for proper cell function. For example, NO is essential for the regulation of vascular tone while superoxide is necessary for proper immune function [1]. Under physiological conditions, a balance exists between the level of ROS produced during normal cellular metabolism and the level of endogenous antioxidants, which serve to protect tissues from oxidative damage. Disruption of this balance, either through increased production of ROS or decreased levels of antioxidants, produces a condition referred to as oxidative stress and leads to variety of pathological conditions including cardiovascular diseases, neurological disorders, lung pathologies, and accelerated aging (reviewed in 2, 3, 4).
Normal cellular metabolism involves the production of reactive oxygen species [5]. Superoxide (O2−) produced from a one-electron reduction of oxygen can undergo either spontaneous or enzyme-catalyzed dismutation to hydrogen peroxide (H2O2) or can react with nitric oxide (NO) to form the toxic product peroxynitrite (ONOO−, Fig. 1). Either the combination of H2O2 with metal ions (iron) or the breakdown of ONOO− can produce the highly toxic hydroxyl radical (•OH). These ROS can react with a variety of cellular macromolecules such as lipids, proteins, DNA, and [Fe-S]4 centers, leading to the disruption of cell membranes, inappropriate activation or inactivation of enzymes, and genetic mutations. Therefore, persistence of these diverse ROS in and around cells and tissues can have severe pathophysiological consequences.
To protect against oxidative damage, organisms have developed a variety of antioxidant defenses that include metal sequestering proteins, use of compounds such as vitamin C and vitamin E, and specialized antioxidant enzymes. One family of antioxidant enzymes, the superoxide dismutases (SOD), function to remove damaging ROS from the cellular environment by catalyzing the dismutation of two superoxide radicals to hydrogen peroxide and oxygen (Fig. 1) 6, 7, 8. This reaction displays pseudo first-order kinetics and is diffusion limited (k = 3 × 109 M−1 s−1) [9]. In eukaryotic cells, two intracellular superoxide dismutases exist: the Cu,ZnSOD [6] and the MnSOD [10]. Cu,ZnSOD is the major intracellular SOD. It exists as a 32 kDa homodimer and is present in the cytoplasm and nucleus of every cell type examined, where it acts as a bulk scavenger of superoxide 11, 12. The MnSOD is a 96 kDa homotetramer and is located primarily in the mitochondrial matrix 10, 12, 13. The loss or dysfunction of either Cu,ZnSOD or MnSOD has been associated with ROS-mediated pathologies. For example, mutated Cu,ZnSOD proteins have been linked to instances of amyotrophic lateral sclerosis [14] while loss of MnSOD has been associated with neonatal death [15].
Section snippets
Biochemical and molecular characteristics of EC-SOD
In 1982, a third SOD isozyme was discovered by Marklund and coworkers and termed extracellular superoxide dismutase (EC-SOD), as it was shown to be the predominant SOD in extracellular fluids such as lymph, synovial fluid, and plasma 16, 17. EC-SOD is a slightly hydrophobic glycoprotein with an apparent molecular weight of 135,000 kDa [8], although some species-specific differences in molecular weight do exist 18, 19. EC-SOD is present in various organisms as a tetramer 20, 21 or, less
Vascular-related diseases
EC-SOD is highly expressed in blood vessels, particularly arterial walls 87, 88, 89, and is the predominant form of SOD in the aortas of baboons and humans, constituting up to 70% of the SOD activity in this tissue [89]. Vascular smooth muscle cells (VSMC) have been shown to secrete large amounts of EC-SOD and it is thought that these cells are the principal source of the enzyme in the vascular wall [88]. The major portion of EC-SOD in the vasculature primarily exists in the extracellular
Regulation of EC-SOD in brain tissue
Increasing evidence suggests that oxidative stress plays a central role in a variety of neurological disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Huntingdon's disease, and Parkinson's disease (reviewed in 3, 147). Thus, the proper function of brain antioxidant mechanisms may be of considerable importance in the prevention of certain neurological disorders.
EC-SOD protein expression patterns in the mouse brain suggest that this enzyme is primarily localized in the
Rheumatoid arthritis
Accumulated evidence suggests that reactive oxygen species play an important role in inflammatory joint disease. Accumulation of inflammatory cells, particularly neutrophils, in the synovial fluid between joints is consistently observed in patients with rheumatoid arthritis. Activation of accumulated neutrophils in the synovial fluid produces superoxide anions, which can react with other cellular components such as iron to produce additional ROS. Early studies by Marklund and coworkers [17]
EC-SOD in development and aging
A recent theory as to why we age suggests that the process of aging may be due, in part, to the gradual overwhelming of endogenous antioxidant defenses by chronic metabolic stress [171]. Many of the diseases already described are associated with oxidative stress and are known to occur more frequently in older populations. Therefore, age-related changes in antioxidant defense mechanisms such as EC-SOD may determine how rapidly we age as well as the number and severity of age-related diseases we
EC-SOD in the lung
Maintaining the balance between ROS/RNS and antioxidants in the lung is required for proper organ function—maybe even more critical than in many of the organs systems already described—since airways are uniquely exposed to relatively higher levels of oxygen than most other tissues [1]. Highly localized production of low levels of ROS/RNS are essential to normal physiological functions in the lung, such as smooth muscle relaxation in airways and blood vessels and immune responses. Furthermore,
Therapeutic applications of EC-SOD
A considerable number of studies have suggested that the administration of a wide variety of enzymatic and nonenzymatic antioxidants can protect against oxidant-induced tissue injury both in animal models and in the human patient. Since EC-SOD levels are decreased in several diseases, it is interesting to entertain the idea of EC-SOD as a potential target for therapy to improve antioxidant capacity and restore the free radical balance. Studies have shown that the half-life of EC-SOD in the
Acknowledgements
This work was supported in part by the National Institutes of Health Grant RO1 HL63700 and a grant from the Pittsburgh Foundation (to T. D. O.).
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