The Redox Enzyme p66Shc Contributes to Diabetes and Ischemia-Induced Delay in Cutaneous Wound Healing
- Gian Paolo Fadini1,
- Mattia Albiero1,
- Lisa Menegazzo1,
- Elisa Boscaro1,
- Elisa Pagnin1,
- Elisabetta Iori1,
- Chiara Cosma2,
- Annunziata Lapolla2,
- Vittorio Pengo3,
- Massimo Stendardo4,
- Carlo Agostini1,
- Pier Giuseppe Pelicci4,
- Marco Giorgio4 and
- Angelo Avogaro1
- 1Department of Clinical and Experimental Medicine, University of Padova Medical School, Padova, Italy;
- 2Department of Surgical and Medical Sciences, University of Padova Medical School, Padova, Italy;
- 3Department of Cardiac, Vascular and Thoracic Sciences, University of Padova, Medical School, Padova, Italy;
- 4European Institute of Oncology, Milan, Italy.
- Corresponding author: Gian Paolo Fadini, gianpaolofadini{at}hotmail.com.
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G.P.F. and M.A. contributed equally to this work.
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.
RESEARCH DESIGN AND 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 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 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 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 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.
Footnotes
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- Received November 24, 2009.
- Accepted June 9, 2010.
- © 2010 by the American Diabetes Association.
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