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Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice.

Demyanenko IA, Popova EN, Zakharova VV, Ilyinskaya OP, Vasilieva TV, Romashchenko VP, Fedorov AV, Manskikh VN, Skulachev MV, Zinovkin RA, Pletjushkina OY, Skulachev VP, Chernyak BV - Aging (Albany NY) (2015)

Bottom Line: This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlierin vitro.The Transforming Growth Factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds.Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.

ABSTRACT
The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlierin vitro. The Transforming Growth Factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds.

No MeSH data available.


Related in: MedlinePlus

SkQ1 prevents TNF-induced decomposition of the endothelial cell-to-cell contacts containing VE-cadherin in vitroEA.hy926 cells were incubated for 4d with 20 nM SkQ1, 1 mM NAC or 0.1 mM Trolox and treated with 5 ng/ml TNF for 24h. (a) Detection of VE-cadherin (green), f-actin (red) and nuclei (blue). Bar, 15 μm. (b) Paracellular permeability assay in the cell monolayer using TRITC-dextran. (c) Representative immunoblotting of VE-cadherin, and (d) its quantification. “c” - untreated cells. Data are presented as mean ± SEM; N=4;*P < 0.05 for SkQ1+TNF-treated versus TNF treated samples; ‡P < 0.001 for the TNF treated versus untreated cells.
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Figure 5: SkQ1 prevents TNF-induced decomposition of the endothelial cell-to-cell contacts containing VE-cadherin in vitroEA.hy926 cells were incubated for 4d with 20 nM SkQ1, 1 mM NAC or 0.1 mM Trolox and treated with 5 ng/ml TNF for 24h. (a) Detection of VE-cadherin (green), f-actin (red) and nuclei (blue). Bar, 15 μm. (b) Paracellular permeability assay in the cell monolayer using TRITC-dextran. (c) Representative immunoblotting of VE-cadherin, and (d) its quantification. “c” - untreated cells. Data are presented as mean ± SEM; N=4;*P < 0.05 for SkQ1+TNF-treated versus TNF treated samples; ‡P < 0.001 for the TNF treated versus untreated cells.

Mentions: Compromised wound healing in old mice could be related to the increased inflammatory status. As we showed earlier, the levels of pro-inflammatory cytokines IL-6 and TNF in the blood were elevated in old animals and SkQ1 had no effect on these markers [11]. These data indicate that anti-inflammatory action of SkQ1 in the models of chronic wounds could be implemented in the tissues affected by an excessive inflammation. We have investigated the mechanisms of the possible anti-inflammatory action of SkQ1 in the culture of endothelial cells EA.hy926. These cells form typical epithelial monolayer with cell-to-cell contacts containing VE- cadherin (Fig. 5a).


Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice.

Demyanenko IA, Popova EN, Zakharova VV, Ilyinskaya OP, Vasilieva TV, Romashchenko VP, Fedorov AV, Manskikh VN, Skulachev MV, Zinovkin RA, Pletjushkina OY, Skulachev VP, Chernyak BV - Aging (Albany NY) (2015)

SkQ1 prevents TNF-induced decomposition of the endothelial cell-to-cell contacts containing VE-cadherin in vitroEA.hy926 cells were incubated for 4d with 20 nM SkQ1, 1 mM NAC or 0.1 mM Trolox and treated with 5 ng/ml TNF for 24h. (a) Detection of VE-cadherin (green), f-actin (red) and nuclei (blue). Bar, 15 μm. (b) Paracellular permeability assay in the cell monolayer using TRITC-dextran. (c) Representative immunoblotting of VE-cadherin, and (d) its quantification. “c” - untreated cells. Data are presented as mean ± SEM; N=4;*P < 0.05 for SkQ1+TNF-treated versus TNF treated samples; ‡P < 0.001 for the TNF treated versus untreated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: SkQ1 prevents TNF-induced decomposition of the endothelial cell-to-cell contacts containing VE-cadherin in vitroEA.hy926 cells were incubated for 4d with 20 nM SkQ1, 1 mM NAC or 0.1 mM Trolox and treated with 5 ng/ml TNF for 24h. (a) Detection of VE-cadherin (green), f-actin (red) and nuclei (blue). Bar, 15 μm. (b) Paracellular permeability assay in the cell monolayer using TRITC-dextran. (c) Representative immunoblotting of VE-cadherin, and (d) its quantification. “c” - untreated cells. Data are presented as mean ± SEM; N=4;*P < 0.05 for SkQ1+TNF-treated versus TNF treated samples; ‡P < 0.001 for the TNF treated versus untreated cells.
Mentions: Compromised wound healing in old mice could be related to the increased inflammatory status. As we showed earlier, the levels of pro-inflammatory cytokines IL-6 and TNF in the blood were elevated in old animals and SkQ1 had no effect on these markers [11]. These data indicate that anti-inflammatory action of SkQ1 in the models of chronic wounds could be implemented in the tissues affected by an excessive inflammation. We have investigated the mechanisms of the possible anti-inflammatory action of SkQ1 in the culture of endothelial cells EA.hy926. These cells form typical epithelial monolayer with cell-to-cell contacts containing VE- cadherin (Fig. 5a).

Bottom Line: This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlierin vitro.The Transforming Growth Factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds.Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.

ABSTRACT
The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlierin vitro. The Transforming Growth Factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds.

No MeSH data available.


Related in: MedlinePlus