DNA-Damage and NAD+-Depletion are Initial Events in Oxygen Radical Induced Islet Cell Death
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Previous studies in vitro and in animal models indicate that reactive oxygen intermediates (ROI) contribute to the destruction of pancreatic islet cells in the pathogenesis of insulin dependent diabetes (Mendola et al., 1989; Rabinovitch et al., 1992). During islet inflammation endothelial cells and infiltrating macrophages are thought to release cyto-toxic amounts ROI (Zweier et al., 1988; Brenner et al., 1993). In addition it was shown, that islet cells are highly susceptible to ROI since they possess only low levels of oxygen radical defense systems (Grankvist et al., 1981; Malaisse et al., 1982). We recently have described an in vitro model of oxygen-radical induced islet cell death where ROI are generated by xanthine oxidase in the presence of hypoxanthine (Burkart et al., 1992). In the present study we investigated the initial events of ROI-induced pancreatic islet cell destruction. We observed that DNA strand breaks and the activation of poly(ADP-ribose) polymerase in islet cell nuclei are prominent early consequences of ROI action. The subsequent islet cell death occured several hours after ROI treatment, which appeared to result from depletion of cellular NAD+ pools. Inhibition of poly(ADP-ribose) polymerase by nicotinamide resulted in the preservation of the NAD+ pool and in islet cell survival.
KeywordsIslet Cell Xanthine Oxidase Pancreatic Islet Cell Reactive Oxygen Intermediate PARP Activation
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- Molinete, M., Verneulen, W., Bürkle, A., Ménissier-de Murcia, J., Küpper, J. H., Hoeijmakers, J. H. J., and de Murcia, G., 1993, Overproduction of the poly(ADP-ribose)polymerase DNA-binding domain blocks alkylation-induced DNA repair synthesis in mammalian cells, EMBO J. 12:2109–2117.PubMedGoogle Scholar
- Parks, D. A., and Granger, D. N., 1986, Xanthine oxidase: biochemistry, distribution and physiology, Acta Phys. Scand. (Suppl. 548):87-99.Google Scholar
- Radons, J., Heller, B., Bürkle, A., Hartmann, B., Rodriguez, M.-L., Kröncke, K.-D., Burkart, V., and Kolb, H., 1994, Nitric oxide toxicity in islet cells involves poly(ADP-ribose) polymerase activation and concomitant NAD depletion, Biochem. Biophys. Res. Comm. 199:1270–1277.PubMedCrossRefGoogle Scholar