Mitochondria-Targeted Antioxidant SkQ1 Improves Dermal Wound Healing in Genetically Diabetic Mice.

Ilya A Demyanenko,Vlada V Zakharova,Olga P Ilyinskaya,Olga Yu Pletjushkina,Artem V Fedorov,Boris V Chernyak,Roman A Zinovkin,Tamara V Vasilieva,Ekaterina N Popova,Vladimir P Skulachev,Vasily N Manskikh

doi:10.1155/2017/6408278

Abstract

Oxidative stress is widely recognized as an important factor in the delayed wound healing in diabetes. However, the role of mitochondrial reactive oxygen species in this process is unknown. It was assumed that mitochondrial reactive oxygen species are involved in many wound-healing processes in both diabetic humans and animals. We have applied the mitochondria-targeted antioxidant 10-(6′-plastoquinonyl)decyltriphenylphosphonium (SkQ1) to explore the role of mitochondrial reactive oxygen species in the wound healing of genetically diabetic mice. Healing of full-thickness excisional dermal wounds in diabetic C57BL/KsJ-db−/db− mice was significantly enhanced after long-term (12 weeks) administration of SkQ1. SkQ1 accelerated wound closure and stimulated epithelization, granulation tissue formation, and vascularization. On the 7th day after wounding, SkQ1 treatment increased the number of α-smooth muscle actin-positive cells (myofibroblasts), reduced the number of neutrophils, and increased macrophage infiltration. SkQ1 lowered lipid peroxidation level but did not change the level of the circulatory IL-6 and TNF. SkQ1 pretreatment also stimulated cell migration in a scratch-wound assay in vitro under hyperglycemic condition. Thus, a mitochondria-targeted antioxidant normalized both inflammatory and regenerative phases of wound healing in diabetic mice. Our results pointed to nearly all the major steps of wound healing as the target of excessive mitochondrial reactive oxygen species production in type II diabetes.

Highlights

Impaired wound healing and chronic wounds are a significant source of complications of diabetes mellitus
New-formed connective tissue of SkQ1-treated db/db mice consisted of more mature and regularly oriented bundles of collagen fibers compared to the granulation tissue of control animals (Figures 2(a) and 2(b) and Figure 3(a))
SkQ1 induced the dramatic increase in content of α-smooth muscle actin (α-SMA)-positive fibroblast-like cells referred to as myofibroblasts (Figures 3(b) and 3(d)). These cells play an important role in the formation and maturation of the granulation tissue due to increased formation of extracellular matrix molecules and growth factors

Summary

Introduction

Impaired wound healing and chronic wounds are a significant source of complications of diabetes mellitus. Wound healing is a complex sequence of cellular and molecular processes consisting of inflammation, formation of the granulation tissue (including myofibroblast accumulation, extracellular matrix synthesis, and angiogenesis), reepithelialization, and tissue remodeling. The impact of diabetes is widespread and pleiotropic, affecting the majority of cells and mechanisms involved in the repair process. These in particular include prolonged and exacerbated inflammatory stage, inadequate expression of growth factors at the site of injury, impaired angiogenesis, dysfunction of fibroblasts and epidermal cells, and impaired ability of bone marrow progenitor cells to migrate to the lesion [1]. Oxidative stress is recognized as a key participant in the development of many diabetic complications. Oxidative stress in diabetes may be involved in most of the above-

Methods

Results

Conclusion