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Molecular Medicine

, Volume 20, Issue 1, pp 363–371 | Cite as

Activation of Poly(ADP-Ribose) Polymerase-1 Delays Wound Healing by Regulating Keratinocyte Migration and Production of Inflammatory Mediators

  • Tarek El-Hamoly
  • Csaba Hegedűs
  • Petra Lakatos
  • Katalin Kovács
  • Péter Bai
  • Mona A. El-Ghazaly
  • Ezzeddin S. El-Denshary
  • Éva Szabó
  • László Virág
Research Article

Abstract

Poly(ADP-ribosyl)ation (PARylation) is a protein modification reaction regulating various diverse cellular functions ranging from metabolism, DNA repair and transcription to cell death. We set out to investigate the role of PARylation in wound healing, a highly complex process involving various cellular and humoral factors. We found that topically applied poly(ADP-ribose) polymerase (PARP) inhibitors 3-aminobenzamide and PJ-34 accelerated wound closure in a mouse model of excision wounding. Moreover, wounds also closed faster in PARP-1 knockout mice as compared with wild-type littermates. Immunofluorescent staining for poly(ADP-ribose) (PAR) indicated increased PAR synthesis in scattered cells of the wound bed. Expression of interleukin (IL)-6, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase and matrix metalloproteinase-9 was lower in the wounds of PARP-1 knockout mice as compared with control, and expression of IL-1 β, cyclooxygenase-2, TIMP-1 and -2 also were affected. The level of nitrotyrosine (a marker of nitrating stress) was lower in the wounds of PARP-1 knockout animals as compared with controls. In vitro scratch assays revealed significantly faster migration of keratinocytes treated with 3-aminobenzamide or PJ34 as compared with control cells. These data suggest that PARylation by PARP-1 slows down the wound healing process by increasing the production of inflammatory mediators and nitrating stress and by slowing the migration of keratinocytes.

Notes

Acknowledgments

This research was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TAMOP 4.2.4.A/2-11/1-2012-0001 National Excellence Program. Direct costs of this study were supported by the Hungarian Science Research Fund (OTKA K82009, K112336 and K108308) and by the Faculty of Medicine, University of Debrecen (Bridging Fund).

Supplementary material

10020_2014_2001363_MOESM1_ESM.pdf (380 kb)
Supplementary material, approximately 380 KB.

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© The Author(s) 2014

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Authors and Affiliations

  • Tarek El-Hamoly
    • 1
    • 2
    • 3
  • Csaba Hegedűs
    • 1
  • Petra Lakatos
    • 1
  • Katalin Kovács
    • 1
    • 4
  • Péter Bai
    • 1
    • 5
    • 6
  • Mona A. El-Ghazaly
    • 2
  • Ezzeddin S. El-Denshary
    • 3
  • Éva Szabó
    • 7
  • László Virág
    • 1
    • 4
  1. 1.Department of Medical Chemistry, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  2. 2.Drug Radiation Research DepartmentNational Centre for Radiation Research and Technology, Atomic Energy AuthorityCairoEgypt
  3. 3.Department of Pharmacology & Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
  4. 4.MTA-DE Cell Biology and Signaling Research GroupDebrecenHungary
  5. 5.MTA-DE Lendület Laboratory of Cellular Metabolism Research GroupDebrecenHungary
  6. 6.Research Center for Molecular MedicineUniversity of DebrecenDebrecenHungary
  7. 7.Department of Dermatology, Faculty of MedicineUniversity of DebrecenDebrecenHungary

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