title: The redox enzyme p66Shc contributes to diabetes and ischemia-induced delay in cutaneous wound healing.
abstract: OBJECTIVE
  The redox enzyme p66Shc produces hydrogen peroxide and triggers proapoptotic signals. Genetic deletion of p66Shc prolongs life span and protects against oxidative stress. In the present study, we evaluated the role of p66Shc in an animal model of diabetic wound healing.
  
  
  METHODS
  Skin wounds were created in wild-type (WT) and p66Shc(-/-) control and streptozotocin-induced diabetic mice with or without hind limb ischemia. Wounds were assessed for collagen content, thickness and vascularity of granulation tissue, apoptosis, reepithelialization, and expression of c-myc and beta-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 beta-catenin. These nonhealing 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 of diabetes duration and in both SV129 and C57BL/6 genetic backgrounds. Deletion of p66Shc reversed nonhealing features, with increased collagen content and granulation tissue thickness, and reduced apoptosis and expression of c-myc and beta-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 and 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 diabetes complication.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Padova Medical School, Padova, Italy. gianpaolofadini@hotmail.com
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Fadini
authors.forename: Mattia
authors.initials: M
authors.lastname: Albiero
authors.forename: Lisa
authors.initials: L
authors.lastname: Menegazzo
authors.forename: Elisa
authors.initials: E
authors.lastname: Boscaro
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iori
authors.forename: Chiara
authors.initials: C
authors.lastname: Cosma
authors.forename: Annunziata
authors.initials: A
authors.lastname: Lapolla
authors.forename: Vittorio
authors.initials: V
authors.lastname: Pengo
authors.forename: Massimo
authors.initials: M
authors.lastname: Stendardo
authors.forename: Carlo
authors.initials: C
authors.lastname: Agostini
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D010084:Oxidation-Reduction; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C002744:3-nitrotyrosine; D014443:Tyrosine; D001120:Arginine; C062187:pentosidine; D008239:Lysine