Polyadenosine diphosphate-ribose polymerase inhibition modulates skeletal muscle injury following ischemia reperfusion.
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.
Hua
Hong T
HT
Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA 20114, USA.
Albadawi
Hassan
H
Entabi
Fateh
F
Conrad
Mark
M
Stoner
Michael C
MC
Meriam
Bryan T
BT
Sroufe
Ramses
R
Houser
Stuart
S
Lamuraglia
Glenn M
GM
Watkins
Michael T
MT
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
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