title: How the location of superoxide generation influences the β-cell response to nitric oxide.
abstract: Cytokines impair the function and decrease the viability of insulin-producing β-cells by a pathway that requires the expression of inducible nitric oxide synthase (iNOS) and generation of high levels of nitric oxide. In addition to nitric oxide, excessive formation of reactive oxygen species, such as superoxide and hydrogen peroxide, has been shown to cause β-cell damage. Although the reaction of nitric oxide with superoxide results in the formation of peroxynitrite, we have shown that β-cells do not have the capacity to produce this powerful oxidant in response to cytokines. When β-cells are forced to generate peroxynitrite using nitric oxide donors and superoxide-generating redox cycling agents, superoxide scavenges nitric oxide and prevents the inhibitory and destructive actions of nitric oxide on mitochondrial oxidative metabolism and β-cell viability. In this study, we show that the β-cell response to nitric oxide is regulated by the location of superoxide generation. Nitric oxide freely diffuses through cell membranes, and it reacts with superoxide produced within cells and in the extracellular space, generating peroxynitrite. However, only when it is produced within cells does superoxide attenuate nitric oxide-induced mitochondrial dysfunction, gene expression, and toxicity. These findings suggest that the location of radical generation and the site of radical reactions are key determinants in the functional response of β-cells to reactive oxygen species and reactive nitrogen species. Although nitric oxide is freely diffusible, its biological function can be controlled by the local generation of superoxide, such that when this reaction occurs within β-cells, superoxide protects β-cells by scavenging nitric oxide.
authors: From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and kbroniow@mcw.edu.
authors: Katarzyna A
authors: KA
authors: Broniowska
authors: From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and.
authors: Bryndon J
authors: BJ
authors: Oleson
authors: From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and.
authors: Jennifer
authors: J
authors: McGraw
authors: From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and.
authors: Aaron
authors: A
authors: Naatz
authors: the Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida 32610.
authors: Clayton E
authors: CE
authors: Mathews
authors: From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and jcorbett@mcw.edu.
authors: John A
authors: JA
authors: Corbett
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D017382:Reactive Oxygen Species; D013481:Superoxides; D009569:Nitric Oxide; D009584:Nitrogen
keywords: Beta Cell (B-cell); Cytokine; Diabetes; Nitric Oxide; Oxidative Stress; Peroxynitrite; Type 1 Diabetes
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