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Title: Endothelial Antioxidant-1: A key mediator of Copper-dependent wound healing in vivo

Here, Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remains elusive. Cu chaperone Antioxidant-1 (Atox1) in the cytosol supplies Cu to the secretory enzymes such as lysyl oxidase (LOX) while Atox1 in the nucleus functions as a Cu-dependent transcription factor. Using cutaneous wound healing model, here we show that Cu content (by X-ray Fluorescence Microscopy) and nuclear Atox1 are increased after wounding, and that wound healing with and without Cu treatment is impaired in Atox1 -/ - mice. Experiments using endothelial cell (EC)-specific Atox1 -/ - mice and gene transfer of nuclear-target Atox1 in Atox1 -/ - mice reveal that Atox1 in ECs as well as transcription factor function of Atox1 are required for wound healing. Mechanistically, Atox1 -/ - mice show reduced Atox1 target proteins such as p47phox NADPH oxidase and cyclin D1 as well as extracellular matrix Cu enzyme LOX activity in wound tissues. This in turn results in reducing O 2 - production in ECs, NFkB activity, cell proliferation and collagen formation, thereby inhibiting angiogenesis, macrophage recruitment and extracellular matrix maturation. Our findings suggest that Cu-dependent transcription factor/Cu chaperone Atox1 in ECs plays an essential role to sense Cumore » to accelerate wound angiogenesis and healing.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [3] ;  [3] ;  [4] ;  [2] ;  [2] ;  [1] ;  [2]
  1. Univ. of Illinois at Chicago, Chicago, IL (United States)
  2. Univ. of Illinois at Chicago, Chicago, IL (United States); Jess Brown Veterans Affairs Medical Center, Chicago, IL (United States)
  3. Argonne National Lab. (ANL), Argonne, IL (United States)
  4. Univ. of Wisconsin, Madison, WI (United States)
Publication Date:
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1333007