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Diabetes 54:2109-2116, 2005
© 2005 by the American Diabetes Association, Inc.

Overexpression of Glutathione Peroxidase With Two Isoforms of Superoxide Dismutase Protects Mouse Islets From Oxidative Injury and Improves Islet Graft Function

Tharun B. Mysore1, Trixie A. Shinkel1, James Collins2, Evelyn J. Salvaris1, Nella Fisicaro1, Lisa J. Murray-Segal1, Lucinda E.A. Johnson1, Diana A. Lepore1, Stacey N. Walters2, Rebecca Stokes2, Abhilash P. Chandra2, Philip J. O’Connell2, Anthony J.F. d’Apice1,3, and Peter J. Cowan1,3

1 Immunology Research Centre, St. Vincent’s Hospital, Melbourne, Australia
2 Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia
3 Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Melbourne, Australia

Primary nonfunction of transplanted islets results in part from their sensitivity to reactive oxygen species (ROS) generated during the isolation and transplantation process. Our aim was to examine whether coexpression of antioxidant enzymes to detoxify multiple ROS increased the resistance of mouse islets to oxidative stress and improved the initial function of islet grafts. Islets from transgenic mice expressing combinations of human copper/zinc superoxide dismutase (SOD), extracellular SOD, and cellular glutathione peroxidase (Gpx-1) were subjected to oxidative stress in vitro. Relative viability after hypoxanthine/xanthine oxidase treatment was as follows: extracellular SOD + Gpx-1 + Cu/Zn SOD > extracellular SOD + Gpx-1 > extracellular SOD > wild type. Expression of all three enzymes was the only combination protective against hypoxia/reoxygenation. Islets from transgenic or control wild-type mice were then transplanted into streptozotocin-induced diabetic recipients in a syngeneic marginal islet mass model, and blood glucose levels were monitored for 7 days. In contrast to single- and double-transgenic grafts, triple-transgenic grafts significantly improved control of blood glucose compared with wild type. Our results indicate that coexpression of antioxidant enzymes has a complementary beneficial effect and may be a useful approach to reduce primary nonfunction of islet grafts.

Address correspondence and reprint requests to Peter J. Cowan, PhD, Immunology Research Centre, St. Vincent’s Hospital Melbourne, P.O. Box 2900, Fitzroy 3065, Victoria, Australia. E-mail: peter.cowan{at}svhm.org.au

Abbreviations: BGL, blood glucose level; FOX, ferric-xylenol orange; GPI, glycophosphatidyl inositol; Gpx-1, glutathione peroxidase; HX/XO, hypoxanthine/xanthine oxidase; IFN-{gamma}, interferon-{gamma}; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; ROS, reactive oxygen species; SOD, superoxide dismutase


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