title: Polyadenosine diphosphate-ribose polymerase inhibition modulates skeletal muscle injury following ischemia reperfusion.
abstract: OBJECTIVE
  Polyadenosine diphosphate-ribose polymerase (PARP) has been implicated as a mediator of inflammation and tissue necrosis in murine models of human stroke and myocardial infarction. This study was designed to determine whether PARP modulates skeletal muscle injury and cytokine-growth factor levels during ischemia-reperfusion.
  
  
  METHODS
  Prospective controlled animal study.
  
  
  METHODS
  Medical school-affiliated university hospital.
  
  
  METHODS
  Mice were divided into 2 groups-treated (PJ) and untreated; all mice were subjected to unilateral hind limb tourniquet ischemia followed by 4 or 48 hours of reperfusion. In treated mice, PJ34, an ultrapotent-specific PARP inhibitor was given immediately before ischemia and prior to reperfusion. A group of PARP-1 knockout mice (PARP-/-) were also subjected to hind limb ischemia followed by 48 hours of reperfusion.
  
  
  METHODS
  After ischemia-reperfusion, muscle was harvested for measurement of edema, viability, cytokine, and vascular endothelial growth factor content.
  
  
  RESULTS
  The PJ34-treated mice had increased skeletal muscle viability when compared with the untreated mice after 4 and 48 hours of reperfusion (P<.01). Viability between PARP-/- and PJ34-treated mice were similar at 48 hours of reperfusion (P>.05), and it exceeded that of untreated mice (P<.01). Tissue edema was unaltered by PARP inhibition. Tissue levels of cytokine were only different (P<.05) in PJ34-treated vs untreated mice at 48 hours of reperfusion. Vascular endothelial growth factor levels in PJ34-treated mice were markedly reduced when compared with untreated mice only after 4 hours of reperfusion (P<.01), and in PARP-/- mice (P<.01) at 48 hours of reperfusion.
  
  
  CONCLUSIONS
  Polyadenosine diphosphate-ribose polymerase modulates skeletal muscle viability, cytokine and vascular endothelial growth factor synthesis during reperfusion. Polyadenosine diphosphate-ribose polymerase inhibition may represent a novel method to modulate skeletal muscle ischemia-reperfusion injury.
authors.affiliation: Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA 20114, USA.
authors.forename: Hong T
authors.initials: HT
authors.lastname: Hua
authors.forename: Hassan
authors.initials: H
authors.lastname: Albadawi
authors.forename: Fateh
authors.initials: F
authors.lastname: Entabi
authors.forename: Mark
authors.initials: M
authors.lastname: Conrad
authors.forename: Michael C
authors.initials: MC
authors.lastname: Stoner
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Meriam
authors.forename: Ramses
authors.initials: R
authors.lastname: Sroufe
authors.forename: Stuart
authors.initials: S
authors.lastname: Houser
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Lamuraglia
authors.forename: Michael T
authors.initials: MT
authors.lastname: Watkins
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019743:Chemokines, CXC / Q000378:metabolism; D006614:Hindlimb; D007124:Immunoenzyme Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D010616:Phenanthrenes / Q000494:pharmacology*; D011064:Poly Adenosine Diphosphate Ribose / Q000037:antagonists & inhibitors*; D011446:Prospective Studies; D015427:Reperfusion Injury / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019743:Chemokines, CXC; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D042461:Vascular Endothelial Growth Factor A; D011064:Poly Adenosine Diphosphate Ribose