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Published in: BMC Oral Health 1/2015

Open Access 01-12-2015 | Research article

Effects of dimethyloxalylglycine on wound healing of palatal mucosa in a rat model

Authors: Tingting Zhu, Hee Chul Park, Kyung Mi Son, Hyeong-Cheol Yang

Published in: BMC Oral Health | Issue 1/2015

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Abstract

Background

Rapid wound healing of oral soft tissue may reduce the opportunity of infection and discomfort of patients. Previous studies have demonstrated that enhancement of angiogenesis is an effective way to accelerate wound repair. In this study, to enhance angiogenesis and healing of palatal wounds, dimethyloxalylglycine (DMOG) was applied to a rat palatal wound model. DMOG is known to inhibit oxygen-dependent degradation of hypoxia inducible factor-1 alpha (HIF-1α), which can lead to up-regulation of angiogenesis markers, favoring wound repair. We also evaluated the effects of DMOG on cell migration and HIF-1α expression of rat palatal (RP) cells. Furthermore, mRNA and protein expression of vascular endothelial growth factor (VEGF) were analyzed in DMOG-treated RP cells.

Methods

Primary cultures of rat palatal (RP) cells were obtained from Sprague–Dawley (SD) rats. Effects of DMOG on cell viability and migration of RP cells were evaluated by using a formazan and culture insert, respectively. VEGF mRNA was observed by real-time PCR, and VEGF and HIF-1α proteins were detected by Western blotting. For the animal study, excisional wounds, 3 mm in diameter, were made at the central part of the palate of SD rats. DMOG with hyaluronic acid ointment was topically applied three times during 1 week, and then wound closures were quantitated photographically and histologically.

Results

DMOG was cytotoxic to RP cells at concentrations higher than 2 mM and did not affect cell migration at non-cytotoxic concentrations. mRNA and protein expression of VEGF were significantly stimulated by DMOG treatment. The protein level of HIF-1α was also stabilized in RP cells by DMOG. In the animal study, groups treated with 1 mg/ml DMOG showed an increase of rat palatal wound contractures.

Conclusions

DMOG enhanced wound healing of rat palatal mucosa, which was likely due to the angiogenic effect of the agent.
Literature
1.
go back to reference Ayvazyan A, Morimoto N, Kanda N, Takemoto S, Kawai K, Sakamoto Y, et al. Collagen-gelatin scaffold impregnated with bFGF accelerates palatal wound healing of palatal mucosa in dogs. J Surg Res. 2011;171:e247–57.CrossRefPubMed Ayvazyan A, Morimoto N, Kanda N, Takemoto S, Kawai K, Sakamoto Y, et al. Collagen-gelatin scaffold impregnated with bFGF accelerates palatal wound healing of palatal mucosa in dogs. J Surg Res. 2011;171:e247–57.CrossRefPubMed
2.
go back to reference Zhu T, Park HC, Son KM, Kwon JH, Park JC, Yang HC. Effects of thymosin β4 on wound healing of rat palatal mucosa. Int J Mol Med. 2014;34:816–21.PubMed Zhu T, Park HC, Son KM, Kwon JH, Park JC, Yang HC. Effects of thymosin β4 on wound healing of rat palatal mucosa. Int J Mol Med. 2014;34:816–21.PubMed
3.
4.
go back to reference Efthimiadou A, Asimakopoulos B, Nikolettos N, Giatromanolaki A, Sivridis E, Papachristou DN, et al. Angiogenic effect of intramuscular administration of basic and acidic fibroblast growth factor on skeletal muscles and influence of exercise on muscle angiogenesis. Br J Sports Med. 2006;40:35–9.CrossRefPubMedPubMedCentral Efthimiadou A, Asimakopoulos B, Nikolettos N, Giatromanolaki A, Sivridis E, Papachristou DN, et al. Angiogenic effect of intramuscular administration of basic and acidic fibroblast growth factor on skeletal muscles and influence of exercise on muscle angiogenesis. Br J Sports Med. 2006;40:35–9.CrossRefPubMedPubMedCentral
5.
go back to reference Jośko J, Gwóźdź B, Jedrzejowska-Szypułka H, Hendryk S. Vascular endothelial growth factor (VEGF) and its effect on angiogenesis. Med Sci Monit. 2000;6:1047–52.PubMed Jośko J, Gwóźdź B, Jedrzejowska-Szypułka H, Hendryk S. Vascular endothelial growth factor (VEGF) and its effect on angiogenesis. Med Sci Monit. 2000;6:1047–52.PubMed
6.
go back to reference Sato N, Beitz JG, Kato J, Yamamoto M, Clark JW, Calabresi P, et al. Platelet-derived growth factor indirectly stimulates angiogenesis in vitro. Am J Pathol. 1993;142:1119–30.PubMedPubMedCentral Sato N, Beitz JG, Kato J, Yamamoto M, Clark JW, Calabresi P, et al. Platelet-derived growth factor indirectly stimulates angiogenesis in vitro. Am J Pathol. 1993;142:1119–30.PubMedPubMedCentral
7.
go back to reference Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G. Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal. 2014;12:26.CrossRefPubMedPubMedCentral Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G. Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal. 2014;12:26.CrossRefPubMedPubMedCentral
8.
go back to reference Ferrari G, Cook BD, Terushkin V, Pintucci G, Mignatti P. Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis. J Cell Physiol. 2009;219:449–58.CrossRefPubMedPubMedCentral Ferrari G, Cook BD, Terushkin V, Pintucci G, Mignatti P. Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis. J Cell Physiol. 2009;219:449–58.CrossRefPubMedPubMedCentral
9.
go back to reference Viñals F, Pouysségur J. Transforming Growth Factor β1 (TGF-β1) Promotes Endothelial Cell Survival during In Vitro Angiogenesis via an Autocrine Mechanism Implicating TGF-α Signaling. Mol Cell Biol. 2001;21:7218–30.CrossRefPubMedPubMedCentral Viñals F, Pouysségur J. Transforming Growth Factor β1 (TGF-β1) Promotes Endothelial Cell Survival during In Vitro Angiogenesis via an Autocrine Mechanism Implicating TGF-α Signaling. Mol Cell Biol. 2001;21:7218–30.CrossRefPubMedPubMedCentral
10.
go back to reference Sayan H, Ozacmak VH, Guven A, Aktas RG, Ozacmak ID. Erythropoietin stimulates wound healing and angiogenesis in mice. J Invest Surg. 2006;19:163–73.CrossRefPubMed Sayan H, Ozacmak VH, Guven A, Aktas RG, Ozacmak ID. Erythropoietin stimulates wound healing and angiogenesis in mice. J Invest Surg. 2006;19:163–73.CrossRefPubMed
11.
go back to reference Fan TP, Hu DE, Guard S, Gresham GA, Watling KJ. Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. Br J Pharmacol. 1993;110:43–9.CrossRefPubMedPubMedCentral Fan TP, Hu DE, Guard S, Gresham GA, Watling KJ. Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. Br J Pharmacol. 1993;110:43–9.CrossRefPubMedPubMedCentral
12.
go back to reference Liu JM, Lawrence F, Kovacevic M, Bignon J, Papadimitriou E, Lallemand JY, et al. The tetrapeptide AcSDKP, an inhibitor of primitive hematopoietic cell proliferation, induces angiogenesis in vitro and in vivo. Blood. 2003;101:3014–20.CrossRefPubMed Liu JM, Lawrence F, Kovacevic M, Bignon J, Papadimitriou E, Lallemand JY, et al. The tetrapeptide AcSDKP, an inhibitor of primitive hematopoietic cell proliferation, induces angiogenesis in vitro and in vivo. Blood. 2003;101:3014–20.CrossRefPubMed
13.
go back to reference Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337–40.CrossRefPubMed Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337–40.CrossRefPubMed
14.
go back to reference Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5:343–54.CrossRefPubMed Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5:343–54.CrossRefPubMed
15.
go back to reference Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda). 2004;19:176–82.CrossRef Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda). 2004;19:176–82.CrossRef
17.
go back to reference Agis H, Watzek G, Gruber R. Prolyl hydroxylase inhibitors increase the production of vascular endothelial growth factor by periodontal fibroblasts. J Periodontal Res. 2012;47:165–73.CrossRefPubMed Agis H, Watzek G, Gruber R. Prolyl hydroxylase inhibitors increase the production of vascular endothelial growth factor by periodontal fibroblasts. J Periodontal Res. 2012;47:165–73.CrossRefPubMed
18.
go back to reference Botusan IR, Sunkari VG, Savu O, Catrina AI, Grünler J, Lindberg S, et al. Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A. 2008;105:19426–31.CrossRefPubMedPubMedCentral Botusan IR, Sunkari VG, Savu O, Catrina AI, Grünler J, Lindberg S, et al. Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A. 2008;105:19426–31.CrossRefPubMedPubMedCentral
19.
go back to reference Warnecke C, Griethe W, Weidemann A, Jürgensen JS, Willam C, Bachmann S, et al. Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors. FASEB J. 2003;17:1186–8.PubMed Warnecke C, Griethe W, Weidemann A, Jürgensen JS, Willam C, Bachmann S, et al. Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors. FASEB J. 2003;17:1186–8.PubMed
20.
go back to reference Nangaku M, Izuhara Y, Takizawa S, Yamashita T, Fujii-Kuriyama Y, Ohneda O, et al. A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia. Arterioscler Thromb Vasc Biol. 2007;27:2548–54.CrossRefPubMed Nangaku M, Izuhara Y, Takizawa S, Yamashita T, Fujii-Kuriyama Y, Ohneda O, et al. A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia. Arterioscler Thromb Vasc Biol. 2007;27:2548–54.CrossRefPubMed
21.
go back to reference Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311–22.CrossRefPubMed Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311–22.CrossRefPubMed
22.
go back to reference Marchbank T, Mahmood A, Harten S, Maxwell PH, Playford RJ. Dimethyloxalyglycine stimulates the early stages of gastrointestinal repair processes through VEGF-dependent mechanisms. Lab Invest. 2011;91:1684–94.CrossRefPubMed Marchbank T, Mahmood A, Harten S, Maxwell PH, Playford RJ. Dimethyloxalyglycine stimulates the early stages of gastrointestinal repair processes through VEGF-dependent mechanisms. Lab Invest. 2011;91:1684–94.CrossRefPubMed
23.
go back to reference Vogler M, Vogel S, Krull S, Farhat K, Leisering P, Lutz S, et al. Hypoxia modulates fibroblastic architecture, adhesion and migration: a role for HIF-1α in cofilin regulation and cytoplasmic actin distribution. PLoS One. 2013;8, e69128.CrossRefPubMedPubMedCentral Vogler M, Vogel S, Krull S, Farhat K, Leisering P, Lutz S, et al. Hypoxia modulates fibroblastic architecture, adhesion and migration: a role for HIF-1α in cofilin regulation and cytoplasmic actin distribution. PLoS One. 2013;8, e69128.CrossRefPubMedPubMedCentral
24.
go back to reference Shafighi M, Olariu R, Fathi AR, Djafarzadeh S, Jakob SM, Banic A, et al. Dimethyloxalylglycine stabilizes HIF-1α in cultured human endothelial cells and increases random-pattern skin flap survival in vivo. Plast Reconstr Surg. 2011;128:415–22.CrossRefPubMed Shafighi M, Olariu R, Fathi AR, Djafarzadeh S, Jakob SM, Banic A, et al. Dimethyloxalylglycine stabilizes HIF-1α in cultured human endothelial cells and increases random-pattern skin flap survival in vivo. Plast Reconstr Surg. 2011;128:415–22.CrossRefPubMed
25.
go back to reference Asikainen TM, Ahmad A, Schneider BK, Ho WB, Arend M, Brenner M, et al. Stimulation of HIF-1alpha, HIF-2alpha, and VEGF by prolyl 4-hydroxylase inhibition in human lung endothelial and epithelial cells. Free Radic Biol Med. 2005;38:1002–13.CrossRefPubMed Asikainen TM, Ahmad A, Schneider BK, Ho WB, Arend M, Brenner M, et al. Stimulation of HIF-1alpha, HIF-2alpha, and VEGF by prolyl 4-hydroxylase inhibition in human lung endothelial and epithelial cells. Free Radic Biol Med. 2005;38:1002–13.CrossRefPubMed
26.
go back to reference Elson DA, Ryan HE, Snow JW, Johnson R, Arbeit JM. Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 2000;60:6189–95.PubMed Elson DA, Ryan HE, Snow JW, Johnson R, Arbeit JM. Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 2000;60:6189–95.PubMed
Metadata
Title
Effects of dimethyloxalylglycine on wound healing of palatal mucosa in a rat model
Authors
Tingting Zhu
Hee Chul Park
Kyung Mi Son
Hyeong-Cheol Yang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Oral Health / Issue 1/2015
Electronic ISSN: 1472-6831
DOI
https://doi.org/10.1186/s12903-015-0047-1

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