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Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo.

ABSTRACT: Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remain 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 mouse 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. 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 O₂^- 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 important role to sense Cu to accelerate wound angiogenesis and healing.

SUBMITTER: Das A

PROVIDER: S-EPMC5036036 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo.

Das Archita A Sudhahar Varadarajan V Chen Gin-Fu GF Kim Ha Won HW Youn Seock-Won SW Finney Lydia L Vogt Stefan S Yang Jay J Kweon Junghun J Surenkhuu Bayasgalan B Ushio-Fukai Masuko M Fukai Tohru T

Scientific reports 20160926

Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remain 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 mouse 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 healin ...[more]

PMID: 27666810

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Project description:Delayed wound healing increases the wound's vulnerability to possible infections, which may have lethal outcomes. The treatments available can be effective, but the urgency is not fully encompassed. The drug repositioning strategy proposes effective alternatives for enhancing medical therapies for chronic diseases. Likewise, applying wound dressings as biodegradable membranes is extremely attractive due to their ease of application, therapeutic effectiveness, and feasibility in industrial manufacturing. This article aims to demonstrate the pleiotropic effects during insulin repositioning in wound closure by employing a biopolymeric membrane-type formulation with insulin. We prepared biopolymeric membranes with sodium alginate cross-linked with calcium chloride, supported in a mixture of xanthan gum and guar gum, and plasticized with glycerol and sorbitol. Human insulin was combined with poloxamer 188 as a protein stabilizing agent. Our investigation encompassed physicochemical and mechanical characterization, antioxidant and biological activity through antibacterial tests, cell viability assessments, and scratch assays as an in vitro and in vivo wound model. We demonstrated that our biopolymeric insulin membranes exhibited adequate manipulation and suitable mechanical resistance, transparency, high swelling capability (1100%), and 30% antioxidant activity. Furthermore, they exhibited antibacterial activity (growth inhibition of S. aureus at 85% and P. aeruginosa at 75%, respectively), and insulin promoted wound closure in vitro with a 5.5-fold increase and 72% closure at 24 h. Also, insulin promoted in vivo wound closure with a 3.2-fold increase and 92% closure at 10 days compared with the groups without insulin, and this is the first report that demonstrates this therapeutic effect with two administrations of 0.7 IU. In conclusion, we developed a multifunctional insulin-loaded biopolymeric membrane in this study, with the main activity derived from insulin's role in wound closure and antioxidant activity, augmented by the antimicrobial effect attributed to the polymer poloxamer 188. The synergistic combination of excipients enhances its usefulness and highlights our innovation as a promising material in wound healing materials.

Dataset Information

Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo.

Publications

Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo.

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