Endogenous Defenses against ROS

Superoxide Dismutase

This enzyme catalyzes the dismutation of superoxide to hydrogen peroxide (H2O2):

Several isozymes of SOD exist: (1) Cu/Zn-SOD, a cytosolic form; (2) Mn-SOD, which is localized within mitochondria; and (3) extracellular SOD (ecSOD). The last is released from cells and binds to sulfated polysaccharides along the cell surface. As a result, ecSOD plays a particularly important role in defense against ROS released from leukocytes adherent to the vascular endothelium. Although conflicting results have been reported regarding the ability of exogenous SOD to attenuate microvascular inflammation, these results have been attributed to rapid plasma clearance of the enzyme or a limited ability of this protein to reach intracellular sites of ROS generation. However, the fact that inhibition of endogenous SOD augments micro-vascular oxidative stress in various conditions clearly demonstrates the importance of this enzyme as a defense against ROS.


As shown earlier, dismutation of superoxide results in formation of H2O2. This lipophilic oxidant can be disposed of by catalase, a cytosolic enzyme that degrades H2O2 to water according to the following reaction:

2H2O2 n 2H2O + O2

Catalase was recognized to be an important endogenous antioxidant based on the following observations: Exogenous administration of catalase reduces oxidative stress as well as the degree of microvascular inflammation in various settings, whereas inhibition of endogenous catalase augments both of these responses.


In addition to catalase, H2O2 can also be degraded via glutathione peroxidase. This cytosolic enzyme utilizes reduced glutathione (GSH) as a proton donor to degrade H2O2 to oxidized glutathione (GSSG) and water:

Another cytosolic enzyme, GSH reductase, converts GSSG back to its reduced form. This recycling of glu-tathione plays an important role in microvascular defenses against oxidative stress as interventions that reduce cellular GSH augment both ROS levels and the extent of micro-vascular inflammation.

Nitric Oxide

Under normal conditions, the rate of NO synthesis within endothelial cells is greater than that of O2-. NO avidly interacts with O2- at a rate approximately threefold higher than dismutation of O2- by SOD. The difference between these reaction rates has led to the proposal that the most important physiological role of NO is its antioxidant action. According to this view, inactivation of O2- by NO maintains low oxi-dant levels within cells under normal conditions. However, a marked increase in the rate of O2- generation would result in NO depletion, and therefore oxidative stress.

A growing body of evidence indicates that it is the balance between the cellular levels of oxidants and NO that plays a key role in the development of microvascular inflammation. Interventions that decrease NO or increase ROS levels (i.e., nitric oxide synthase inhibitors, inhibition of endogenous antioxidants) cause arteriolar vasoconstriction, leukocyte-endothelial cell adhesive interactions, and increased vascular permeability. Conversely, administration of exogenous NO or antioxidants (which increase NO or decrease oxidant levels) enhances endothelium-dependent arteriolar vasodilation and attenuates leukocyte adhesion and increases in vascular permeability in various conditions.

Nonenzymatic Antioxidants

Ascorbic acid, vitamin E, lipoic acid, uric acid, bilirubin, and b-carotene are among a group of endogenous free radical scavengers. The antioxidant action of these compounds is due to their ability to donate an electron to an oxidant species, thereby inactivating it. Because transition metals such as iron and copper can react with O2- to form the highly reactive hydroxyl radical (Off), another group of compounds that act as metal chelators also contribute to antioxidant defenses. These compounds include ferritin, ceruloplasmin, and transferrin.

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