The redox enzyme p66Shc contributes to diabetes and ischemia-induced delay in cutaneous wound healing

The redox enzyme p66Shc produces hydrogen peroxide and triggers proapoptotic signals. Genetic deletion of p66Shc prolongs lifespan and protects against oxidative stress. In the present study, we evaluated the role of p66Shc in an animal model of diabetic wound healing. Research design and methods. Skin wounds were created in wild type (WT) and p66Shc−/− control and streptozotocin diabetic mice with or without hind limb ischemia. Wounds were assessed for collagen content, thickness and vascularity of granulation tissue, apoptosis, re-epitelialization, expression of c-myc and β-catenin. Response to hind limb ischemia was also evaluated. Results. Diabetes delayed wound healing in WT mice with reduced granulation tissue thickness and vascularity, increased apoptosis, epithelial expression of c-myc and nuclear localization of β-catenin. These non-healing features were worsened by hind limb ischemia. Diabetes induced p66Shc expression and activation; wound healing was significantly faster in p66Shc-/- than in WT diabetic mice, with or without hind limb ischemia at 1 and 3 months diabetes duration and in both SV129 and C57Bl/6 genetic backgrounds. Deletion of p66Shc reversed non-healing features, with increased collagen content and granulation tissue thickness, reduced apoptosis and expression of c-myc and β-catenin. p66Shc deletion improved response to hind limb ischemia in diabetic mice, in terms of tissue damage, capillary density and perfusion. Migration of p66Shc-/- dermal fibroblasts in vitro was significantly faster than WT fibroblasts under both high glucose or hypoxia. Conclusions. p66Shc is involved in the delayed wound healing process in the setting of diabetes and ischemia. Thus, p66Shc may represent a potential therapeutic target against this disabling diabetic complication