Although XOR has gained special attention because of its suggested involvement in ischemia-reperfusion injury, its relative importance has been challenged by other ROS producers. For example, in the mitochondria, ROS are produced as part of the respiratory oxidative phosphorylation. Mitochondria have also been reported to produce ROS under hypoxic conditions. In this so-called "reductive burst," ROS production is presumed to precede activation of other ROS-producing systems such as XOR and has been implicated in hypoxia-induced increased endothelial permeability and IL-6 production in human umbilical vein endothelial cells (HUVECs).
The NAD(P)H oxidase is another potential source of ROS in endothelial cells. This enzyme complex has been shown to produce ROS in vascular cells, including smooth muscle cells, fibroblasts, and endothelial cells, in a manner similar to the neutrophil NAD(P)H oxidase. However, unlike neutrophils, in which ROS are generated in large amounts in an "oxidative burst," vascular cell NAD(P)H oxidase generates sustained small amounts of ROS believed to be important in signaling and in the pathogenesis of vascular diseases. The NAD(P)H oxidase is also a regulated enzyme, the activity of which can be modulated by changes in one of its subunits, such as pMphox. Activation of NAD(P)H oxidase has been implicated in a variety of vascular diseases, including hypertension.
In considering potential sources of ROS one should keep in mind the aldehyde oxidases, which bear significant homology to xanthine oxidase and are believed to be derived from copies of the XOR gene. This interesting family of oxidases has been shown to metabolize several xeno-biotics. However, their natural substrates remain unknown. Since antibodies directed at XOR protein may cross-react with aldehyde oxidase protein, a note of caution should be raised about conclusions related to XOR in studies using such antibodies. Finally, an important source of ROS in the endothelium is nitric oxide synthase, which is covered in detail in other chapters.
The relative importance of each of the just-mentioned sources of ROS to different types of endothelial injury and vascular diseases needs to be elucidated. Although results obtained in a certain cell type under specific conditions might suggest a major role for one source versus others, most of these ROS-producing systems are likely to be involved in endothelial signaling or injury. Indeed, it is possible that these enzymatic systems might work in concert to mediate different phases of a specific response. For example, hypoxia might rapidly activate p38 through mitochon-drial production of ROS, and p38 in turn will activate XOR, resulting in further production of ROS.
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