title: Activation of poly(ADP-ribose) polymerase-1 delays wound healing by regulating keratinocyte migration and production of inflammatory mediators.
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-1β, 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.
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Drug Radiation Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Tarek
authors.initials: T
authors.lastname: El-Hamoly
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Hegedűs
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Petra
authors.initials: P
authors.lastname: Lakatos
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Kovács
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary MTA-DE Lendület Laboratory of Cellular Metabolism Research Group, Debrecen, Hungary Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Bai
authors.affiliation: Drug Radiation Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt.
authors.forename: Mona A
authors.initials: MA
authors.lastname: El-Ghazaly
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Ezzeddin S
authors.initials: ES
authors.lastname: El-Denshary
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Szabó
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Virág
mesh_terms: D000818:Animals; D002465:Cell Movement; D051546:Cyclooxygenase 2 / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D015603:Keratinocytes / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014945:Wound Healing / Q000502:physiology*
chemical_list: C587672:IL1B protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D019716:Tissue Inhibitor of Metalloproteinase-2; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse