Mitochondria-Targeted Antioxidant SkQ1 Improves Dermal Wound Healing in Genetically Diabetic Mice
Ilya A. Demyanenko
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Search for more papers by this authorVlada V. Zakharova
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Search for more papers by this authorOlga P. Ilyinskaya
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Search for more papers by this authorTamara V. Vasilieva
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Search for more papers by this authorArtem V. Fedorov
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Search for more papers by this authorVasily N. Manskikh
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Institute of Mitoengineering, Lomonosov Moscow State University, Leninskie Gory 1-73, Moscow 119992, Russia msu.ru
Search for more papers by this authorRoman A. Zinovkin
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Institute of Mitoengineering, Lomonosov Moscow State University, Leninskie Gory 1-73, Moscow 119992, Russia msu.ru
Search for more papers by this authorOlga Yu Pletjushkina
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Search for more papers by this authorBoris V. Chernyak
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Search for more papers by this authorVladimir P. Skulachev
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Institute of Mitoengineering, Lomonosov Moscow State University, Leninskie Gory 1-73, Moscow 119992, Russia msu.ru
Search for more papers by this authorCorresponding Author
Ekaterina N. Popova
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Search for more papers by this authorIlya A. Demyanenko
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Search for more papers by this authorVlada V. Zakharova
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Search for more papers by this authorOlga P. Ilyinskaya
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Search for more papers by this authorTamara V. Vasilieva
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Search for more papers by this authorArtem V. Fedorov
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Search for more papers by this authorVasily N. Manskikh
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Institute of Mitoengineering, Lomonosov Moscow State University, Leninskie Gory 1-73, Moscow 119992, Russia msu.ru
Search for more papers by this authorRoman A. Zinovkin
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, Moscow 119234, Russia msu.ru
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Institute of Mitoengineering, Lomonosov Moscow State University, Leninskie Gory 1-73, Moscow 119992, Russia msu.ru
Search for more papers by this authorOlga Yu Pletjushkina
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Search for more papers by this authorBoris V. Chernyak
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Search for more papers by this authorVladimir P. Skulachev
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Institute of Mitoengineering, Lomonosov Moscow State University, Leninskie Gory 1-73, Moscow 119992, Russia msu.ru
Search for more papers by this authorCorresponding Author
Ekaterina N. Popova
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia msu.ru
Search for more papers by this authorAbstract
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.
References
- 1 Gary Sibbald R. and Woo K. Y., The biology of chronic foot ulcers in persons with diabetes, Diabetes/Metabolism Research and Reviews. (2008) 24, S25–S30, https://doi.org/10.1002/dmrr.847, 2-s2.0-44949173228.
- 2 Monnier L., Mas E., Ginet C., Michel F., Villon L., Cristol J. P., and Colette C., Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes, Journal of the American Medical Association. (2006) 295, 1681–1687, https://doi.org/10.1001/jama.295.14.1681, 2-s2.0-33645745733.
- 3 Callaghan M. J., Ceradini D. J., and Gurtner G. C., Hyperglycemia-induced reactive oxygen species and impaired endothelial progenitor cell function, Antioxidants & Redox Signaling. (2005) 7, 1476–1482, https://doi.org/10.1089/ars.2005.7.1476, 2-s2.0-28844434974.
- 4 Folli F., Corradi D., Fanti P., Davalli A., Paez A., Giaccari A., Perego C., and Muscogiuri G., The role of oxidative stress in the pathogenesis of type 2 diabetes mellitus micro- and macrovascular complications: avenues for a mechanistic-based therapeutic approach, Current Diabetes Reviews. (2011) 7, 313–324, https://doi.org/10.2174/157339911797415585.
- 5 Brownlee M., The pathobiology of diabetic complications, Diabetes. (2005) 54, 1615–1625, https://doi.org/10.2337/diabetes.54.6.1615, 2-s2.0-20044376702.
- 6 Giacco F. and Brownlee M., Oxidative stress and diabetic complications, Circulation Research. (2010) 107, 1058–1070, https://doi.org/10.1161/CIRCRESAHA.110.223545, 2-s2.0-78349297565.
- 7 Sharma K., Mitochondrial hormesis and diabetic complications, Diabetes. (2015) 64, 663–672, https://doi.org/10.2337/db14-0874, 2-s2.0-84962070947.
- 8 Houstis N., Rosen E. D., and Lander E. S., Reactive oxygen species have a causal role in multiple forms of insulin resistance, Nature. (2006) 440, 944–948, https://doi.org/10.1038/nature04634, 2-s2.0-33645860825.
- 9 Skulachev M. V., Antonenko Y. N., Anisimov V. N., Chernyak B. V., Cherepanov D. A., Chistyakov V. A., Egorov M. V., Kolosova N. G., Korshunova G. A., Lyamzaev K. G., and Plotnikov E. Y., Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies, Current Drug Targets. (2011) 12, 800–826, https://doi.org/10.2174/138945011795528859, 2-s2.0-79955595082.
- 10 Paglialunga S., Van Bree B., Bosma M., Valdecantos M. P., Amengual-Cladera E., Jörgensen J. A., Van Beurden D., den Hartog G. J., Ouwens D. M., Briedé J. J., and Schrauwen P., Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice, Diabetologia. (2012) 55, 2759–2768, https://doi.org/10.1007/s00125-012-2626-x, 2-s2.0-84866107987.
- 11 Jain S. S., Paglialunga S., Vigna C., Ludzki A., Herbst E. A., Lally J. S., Schrauwen P., Hoeks J., Tupling A. R., Bonen A., and Holloway G. P., High-fat diet–induced mitochondrial biogenesis is regulated by mitochondrial-derived reactive oxygen species activation of CaMKII, Diabetes. (2014) 63, https://doi.org/10.2337/db13-0816, 2-s2.0-84901377446, 24520120, 84901377446.
- 12 Demyanenko I. A., Popova E. N., Zakharova V. V., Ilyinskaya O. P., Vasilieva T. V., Romashchenko V. P., Fedorov A. V., Manskikh V. N., Skulachev M. V., Zinovkin R. A., and Pletjushkina O. Y., Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice, Aging (Albany NY). (2015) 7, 475–485, https://doi.org/10.18632/aging.100772.
- 13 Mihara M. and Uchiyama M., Determination of malonaldehyde precursor in tissues by thiobarbituric acid test, Analytical Biochemistry. (1978) 86, 271–278, 655387.
- 14 Underwood R. A., Gibran N. S., Muffley L. A., Usui M. L., and Olerud J. E., Color subtractive–computer-assisted image analysis for quantification of cutaneous nerves in a diabetic mouse model, The Journal of Histochemistry and Cytochemistry. (2001) 49, 1285–1291, https://doi.org/10.1177/002215540104901011.
- 15 Michaels J., Churgin S. S., Blechman K. M., Greives M. R., Aarabi S., Galiano R. D., and Gurtner G. C., db/db mice exhibit severe wound-healing impairments compared with other murine diabetic strains in a silicone-splinted excisional wound model, Wound Repair and Regeneration. (2007) 15, 665–670, https://doi.org/10.1111/j.1524-475X.2007.00273.x, 2-s2.0-34848870970.
- 16 Tkalčević V. I., Čužić S., Parnham M. J., Pašalić I., and Brajša K., Differential evaluation of excisional non-occluded wound healing in db/db mice, Toxicologic Pathology. (2009) 37, 183–192, https://doi.org/10.1177/0192623308329280, 2-s2.0-67049164147.
- 17 Popova E. N., Pletjushkina O. Y., Dugina V. B., Domnina L. V., Ivanova O. Y., Izyumov D. S., Skulachev V. P., and Chernyak B. V., Scavenging of reactive oxygen species in mitochondria induces myofibroblast differentiation, Antioxidants & Redox Signaling. (2010) 13, 1297–1307, https://doi.org/10.1089/ars.2009.2949, 2-s2.0-77955050606.
- 18 Demianenko I. A., Vasilieva T. V., Domnina L. V., Dugina V. B., Egorov M. V., Ivanova O. Y., Ilinskaya O. P., Pletjushkina O. Y., Popova E. N., Sakharov I. Y., and Fedorov A. V., Novel mitochondria-targeted antioxidants, “Skulachev-ion” derivatives, accelerate dermal wound healing in animals, Biochemistry (Mosc). (2010) 75, 274–280, https://doi.org/10.1134/S000629791003003X, 2-s2.0-77950661317.
- 19 Feillet-Coudray C., Fouret G., Ebabe Elle R., Rieusset J., Bonafos B., Chabi B., Crouzier D., Zarkovic K., Zarkovic N., Ramos J., and Badia E., The mitochondrial-targeted antioxidant MitoQ ameliorates metabolic syndrome features in obesogenic diet-fed rats better than apocynin or allopurinol, Free Radical Research. (2014) 48, 1232–1246, https://doi.org/10.3109/10715762.2014.945079, 2-s2.0-84929994957.
- 20 Eming S. A., Krieg T., and Davidson J. M., Inflammation in wound repair: molecular and cellular mechanisms, The Journal of Investigative Dermatology. (2007) 127, 514–525, https://doi.org/10.1038/sj.jid.5700701, 2-s2.0-33847020833.
- 21 Dovi J. V., He L.-K., and DiPietro L. A., Accelerated wound closure in neutrophil-depleted mice, Journal of Leukocyte Biology. (2003) 73, 448–455, https://doi.org/10.1189/JLB.0802406, 2-s2.0-0037983059.
- 22 Mahadev K., Zilbering A., Zhu L., and Goldstein B. J., Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1B in vivo and enhances the early insulin action cascade, The Journal of Biological Chemistry. (2001) 276, 21938–21942, https://doi.org/10.1074/jbc.C100109200, 2-s2.0-0035877633.
- 23 S. Biosciences, Epigenetic modifications regulate gene expression, Pathways Mag. 2008, March 2017, http://www.sabiosciences.com/pathwaymagazine/pathways8/epigenetic-modifications-regulate-gene-expression.php.
- 24 Gray J. P. and Heart E., Usurping the mitochondrial supremacy: extramitochondrial sources of reactive oxygen intermediates and their role in beta cell metabolism and insulin secretion, Toxicology Mechanisms and Methods. (2010) 20, 167–174, https://doi.org/10.3109/15376511003695181, 2-s2.0-77955284325.
- 25 Leloup C., Tourrel-Cuzin C., Magnan C., Karaca M., Castel J., Carneiro L., Colombani A. L., Ktorza A., Casteilla L., and Pénicaud L., Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion, Diabetes. (2009) 58, 673–681, https://doi.org/10.2337/db07-1056, 2-s2.0-62749103868.
- 26 Robertson R. P., Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes, The Journal of Biological Chemistry. (2004) 279, 42351–42354, https://doi.org/10.1074/jbc.R400019200, 2-s2.0-5644248079.
- 27 Zinovkin R. A., Romaschenko V. P., Galkin I. I., Zakharova V. V., Pletjushkina O. Y., Chernyak B. V., and Popova E. N., Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium, Aging (Albany NY). (2014) 6, 661–674, https://doi.org/10.18632/aging.100685.
- 28 Galkin I. I., Pletjushkina O. Y., Zinovkin R. A., Zakharova V. V., Birjukov I. S., Chernyak B. V., and Popova E. N., Mitochondria-targeted antioxidants prevent TNFα-induced endothelial cell damage, Biochemistry (Moscow). (2014) 79, 124–130, https://doi.org/10.1134/S0006297914020059, 2-s2.0-84894627981.
- 29 Maruyama K., Asai J., Ii M., Thorne T., Losordo D. W., and D’Amore P. A., Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing, The American Journal of Pathology. (2007) 170, 1178–1191, https://doi.org/10.2353/ajpath.2007.060018, 2-s2.0-34247874642.
- 30 Khanna S., Biswas S., Shang Y., Collard E., Azad A., Kauh C., Bhasker V., Gordillo G. M., Sen C. K., and Roy S., Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice, PloS One. (2010) 5, article e9539, https://doi.org/10.1371/journal.pone.0009539, 2-s2.0-77949681013.
- 31 Mirza R. E., Fang M. M., Weinheimer-Haus E. M., Ennis W. J., and Koh T. J., Sustained inflammasome activity in macrophages impairs wound healing in type 2 diabetic humans and mice, Diabetes. (2014) 63, https://doi.org/10.2337/db13-0927, 2-s2.0-84894433435, 24194505, 84894433435.
- 32 Zhou R., Yazdi A. S., Menu P., and Tschopp J., A role for mitochondria in NLRP3 inflammasome activation, Nature. (2011) 469, 221–225, https://doi.org/10.1038/nature09663, 2-s2.0-78651393239.
- 33 Dashdorj A., Jyothi K., Lim S., Jo A., Nguyen M. N., Ha J., Yoon K. S., Kim H. J., Park J. H., Murphy M. P., and Kim S. S., Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines, BMC Medicine. (2013) 11, https://doi.org/10.1186/1741-7015-11-178, 2-s2.0-84881048250.
- 34 Lamers M. L., Almeida M. E. S., Vicente-Manzanares M., Horwitz A. F., and Santos M. F., High glucose-mediated oxidative stress impairs cell migration, PloS One. (2011) 6, article e22865, https://doi.org/10.1371/journal.pone.0022865, 2-s2.0-79961080156.
- 35 Lee C. H., Shah B., Moioli E. K., and Mao J. J., CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model, The Journal of Clinical Investigation. (2010) 120, 3340–3349, https://doi.org/10.1172/JCI43230, 2-s2.0-77956388751.
- 36 Ferraro F., Lymperi S., Méndez-Ferrer S., Saez B., Spencer J. A., Yeap B. Y., Masselli E., Graiani G., Prezioso L., Rizzini E. L., and Mangoni M., Diabetes impairs hematopoietic stem cell mobilization by altering niche function, Science Translational Medicine. (2011) 3, no. 104, article 104ra101, https://doi.org/10.1126/scitranslmed.3002191, 2-s2.0-80054035544, 21998408, 80054035544.
- 37 Albiero M., Poncina N., Tjwa M., Ciciliot S., Menegazzo L., Ceolotto G., de Kreutzenberg S. V., Moura R., Giorgio M., Pelicci P., and Avogaro A., Diabetes causes bone marrow autonomic neuropathy and impairs stem cell mobilization via dysregulated p66Shc and Sirt1, Diabetes. (2014) 63, https://doi.org/10.2337/db13-0894, 2-s2.0-84897895811, 24270983, 84897895811.
- 38 Galimov E. R., Chernyak B. V., Sidorenko A. S., Tereshkova A. V., and Chumakov P. M., Prooxidant properties of p66shc are mediated by mitochondria in human cells, PloS One. (2014) 9, article e86521, https://doi.org/10.1371/journal.pone.0086521, 2-s2.0-84897521291.
- 39 Shipounova I. N., Svinareva D. A., Petrova T. V., Lyamzaev K. G., Chernyak B. V., Drize N. I., and Skulachev V. P., Reactive oxygen species produced in mitochondria are involved in age-dependent changes of hematopoietic and mesenchymal progenitor cells in mice. A study with the novel mitochondria-targeted antioxidant SkQ1, Mechanisms of Ageing and Development. (2010) 131, 415–421, https://doi.org/10.1016/j.mad.2010.06.003, 2-s2.0-77955055308.
- 40 Bitar M. S. and Labbad Z. N., Transforming growth factor-β and insulin-like growth factor-I in relation to diabetes-induced impairment of wound healing, The Journal of Surgical Research. (1996) 61, 113–119, https://doi.org/10.1006/jsre.1996.0090, 2-s2.0-0030059185.
- 41 Gong D., Shi W., Yi S., Chen H., Groffen J., and Heisterkamp N., TGFβ signaling plays a critical role in promoting alternative macrophage activation, BMC Immunology. (2012) 13, https://doi.org/10.1186/1471-2172-13-31, 2-s2.0-84862180623.
- 42 Marrotte E. J., Chen D. D., Hakim J. S., and Chen A. F., Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice, The Journal of Clinical Investigation. (2010) 120, 4207–4219, https://doi.org/10.1172/JCI36858, 2-s2.0-78649820215.
- 43 Skulachev V. P., Anisimov V. N., Antonenko Y. N., Bakeeva L. E., Chernyak B. V., Erichev V. P., Filenko O. F., Kalinina N. I., Kapelko V. I., Kolosova N. G., and Kopnin B. P., An attempt to prevent senescence: a mitochondrial approach, Biochimica et Biophysica Acta - Bioenergetics. (2009) 1787, 437–461, https://doi.org/10.1016/j.bbabio.2008.12.008, 2-s2.0-67349283471.
- 44 Anisimov V. N., Egorov M. V., Krasilshchikova M. S., Lyamzaev K. G., Manskikh V. N., Moshkin M. P., Novikov E. A., Popovich I. G., Rogovin K. A., Shabalina I. G., and Shekarova O. N., Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents, Aging (Albany NY). (2011) 3, 1110–1119, https://doi.org/10.18632/aging.100404.
