Sources of ROS

Xanthine Oxidase

Xanthine dehydrogenase is a cytosolic enzyme that catalyzes the formation of xanthine from hypoxanthine. Activation of proteases may convert this enzyme to xanthine oxidase (XO). Under normal conditions, little XO exists within cells. This enzyme uses molecular oxygen as an electron acceptor (instead of NAD+ as in the case of xanthine dehydrogenase), which results in production of superoxide. A central role for XO in I/R-induced microvascular inflammation has been supported by the observation that XO inhibitors attenuate both venular ROS levels and leukocyte adherence after I/R.

Nitric Oxide Synthase

In some conditions, ROS may be produced by nitric oxide synthase (NOS). This enzyme catalyzes the oxidation of L-arginine to L-citrulline, which results in the production of NO. This reaction requires several cofactors, including NADH and tetrahydrobiopterin (BH4). Limited availability of these cofactors can result in generation of O2- and H2O2 via uncoupling of NOS. For example, BH4 levels are insuf ficient for optimal NOS activity in hypercholesterolemia and in some forms of hypertension, resulting in O2-production by this enzyme. Administration of BH4 to spontaneously hypertensive rats decreased systemic blood pressure, an effect attributed to generalized arteriolar vasodilation resulting from reduced O2- production by NOS.

NADPH Oxidase

This enzyme was first identified as that responsible for superoxide generation during the respiratory burst of activated neutrophils. Because this pathway is capable of producing large amounts of ROS to kill bacteria, adherence of leukocytes to the endothelium as well as emigration of leukocytes to the perivascular space can significantly enhance oxidative stress within the microcirculation. Recent evidence has demonstrated that this enzyme is localized in other cells as well, including endothelial cells, mast cells, platelets, and vascular smooth muscle cells. In these cells, NADPH oxidase generates much lower amounts of O2- than does the neutrophilic enzyme, and likely plays a role in signal transduction rather than bactericidal actions.

Mitochodrial Electron Transport

Approximately 5 percent of molecular oxygen is converted to superoxide during electron transport within mitochondria under normal conditions. A growing body of evidence has shown that superoxide generation increases above this basal rate when O2 levels are reduced. Using fluorescent dyes to detect oxidants, a reduction in PO2 was demonstrated to rapidly increase ROS formation within endothelial cells in vitro. Evidence implicates ubisemiquinone, a free radical associated with complex III of the electron transport chain, as the major site of hypoxia-induced superoxide production. The significance of this finding is the demonstration of a pathway capable of increasing O2- production when O2 levels are reduced; superoxide formation by this route is inversely proportional to O2 levels. In contrast, in the pathways discussed previ ously, the rate of ROS generation is directly proportional to the available O2.

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