Oxygen NADPH Oxidase

Ushio-Fukai M, Nakamura Y (2008) Reactive oxygen species and angiogenesis NADPH oxidase as target for cancer therapy. Cancer Lett 266 37-52 Valentin A, Rosati M, Patenaude DJ, Hatzakis A, Kostrikis LG, Lazanas M (2002) Persistent HIV-1 infection of natural killer cells in patients receiving highly active antiretroviral therapy. Proc Natl Acad Sci U S A 99(10) 7015-7020... 

Superoxide is produced by the NADPH oxidoreduc-tase (oxidase), which is a membrane-bound enzyme complex containing a flavoprotein that catalyses the transfer of single electrons from NADPH in the cytosol to extracellular oxygen. NADPH is mainly supplied by the hexose monophosphate shunt. In resting cells, the oxidase complex is inactive and disassembled, but is rapidly reconstituted and activated by chemotactic mechanisms or phagocytosis (Baggiolini and Thelen, 1991). 

That the oxidative burst is directly involved in the chemical defense of these algae is clear. This reaction can be inhibited by diphenyleneiodonium, a suicide inhibitor of NADPH-oxidase which suppresses both the production of reactive oxygen species and the natural resistance to epiphytic bacteria. In addition a role in the defense against endophytes was indicated, since pre-treatment with oligomeric guluronates resulted in decreased infection of L. digitata with the pathogen Laminariocolax tomentosoides [141]. 

Mitochondria and NADPH Oxidase as Initiators of Oxygen Radical Overproduction in Heart Diseases... 

Historically, leukocyte NADPH oxidase was the first discovered enzyme of this type the existence of this enzyme in neutrophils was reported in 1962-1966 [59-61]. (As the evidence of superoxide production in biological systems has been obtained several years later, at that time the nature of oxygen species produced by leukocytes was of course unknown.) And only about 10 years later, Babior et al. [62] have shown that the activation of human neutrophils resulted in the production of superoxide. The structure of leukocyte NADPH has been widely discussed and well-established [57]. Superoxide production catalyzed by NADPH oxidase is described by Reaction (5) ... 

Holland et al. [125] have shown that the potent vascular smooth muscle cell mitogen and phospholipase A2 activator thrombin stimulated superoxide production in human endothelial cells, which was inhibited by the NADPH oxidase inhibitors. Similarly, thrombin enhanced the production of oxygen species and the expression of )Alphos and Rac2 subunits of NADPH oxidase in VSMCs [126,127]. Greene et al. [128] demonstrated that the activator of NO synthase neuropeptide bradykinin is also able to stimulate NADPH oxidase in VSMCs. Similar to XO, NADPH oxidase enhanced superoxide production in pulmonary artery smooth muscle cells upon exposure to hypoxia [129]. 

Oxidized LDL are considered to be one of the major factors associated with the development of atherosclerosis. The earliest event is the transport of LDL into the arterial wall where LDL, being trapped in subendothelial space, are oxidized by oxygen radicals produced by endothelial and arterial smooth muscle cells. The oxidation of LDL in the arterial wall is affected by various factors including hemodynamic forces such as shear stress and stretch force. Thus, it has been shown [177] that stress force imposed on vascular smooth muscle cells incubated with native LDL increased the MDA formation by about 150% concomitantly with the enhancement of superoxide production. It was suggested that oxidation was initiated by NADPH oxidase-produced superoxide and depended on the presence of metal ions. 

Thus, the mechanism of MT antioxidant activity might be connected with the possible antioxidant effect of zinc. Zinc is a nontransition metal and therefore, its participation in redox processes is not really expected. The simplest mechanism of zinc antioxidant activity is the competition with transition metal ions capable of initiating free radical-mediated processes. For example, it has recently been shown [342] that zinc inhibited copper- and iron-initiated liposomal peroxidation but had no effect on peroxidative processes initiated by free radicals and peroxynitrite. These findings contradict the earlier results obtained by Coassin et al. [343] who found no inhibitory effects of zinc on microsomal lipid peroxidation in contrast to the inhibitory effects of manganese and cobalt. Yeomans et al. [344] showed that the zinc-histidine complex is able to inhibit copper-induced LDL oxidation, but the antioxidant effect of this complex obviously depended on histidine and not zinc because zinc sulfate was ineffective. We proposed another mode of possible antioxidant effect of zinc [345], It has been found that Zn and Mg aspartates inhibited oxygen radical production by xanthine oxidase, NADPH oxidase, and human blood leukocytes. The antioxidant effect of these salts supposedly was a consequence of the acceleration of spontaneous superoxide dismutation due to increasing medium acidity. 

Xanthine oxidase is not the only source of reactive species in ischemia-reoxygenation injury. Another source of oxygen radicals is NADPH oxidase. For example, it has been shown that endothelial NADPH oxidase produced reactive oxygen species in lungs exposed to ischemia [13]. (The role of NADPH oxidase as a producer of oxygen radicals in tissue is considered below.)... 

Itou, T. et al., Oxygen radical generation and expression of NADPH oxidase genes in bottlenose dolphin (Tursiops truncatus) neutrophils, Develop. Comp. Immunol., 25, 47, 2001. 

Phagocytic leukocytes that are exposed to opsonized particles, chemoattractants, or selected cytokines undergo a rapid burst in oxygen consumption and activation of the enzyme responsible for the oxidative metabolic burst, NADPH oxidase (reviewed in ref. 1). Active NADPH oxidase catalyzes the reaction ... 

Figure 9.2. Mechanisms of aminoglycoside toxicity. This schematic representation summarizes the principles of aminoglycoside toxicity discussed in the text. Treatment with the drugs leads to the formation of reactive oxygen species through a redox-active complex with iron and unsaturated fatty acid or by triggering superoxide production by way of NADPH oxidase. An excess of reactive oxygen species, not balanced by intracellular antioxidant systems, will cause an oxidative imbalance potentially severe enough to initiate cell death pathways. Augmenting cellular defenses by antioxidant therapy can reverse the imbalance and restore homeostasis to protect the cell.

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