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Poly ADP-Ribose Polymerase (PARP) Inhibition Modulates Skeletal Muscle Injury Following Ischemia Reperfusion

Hong T. Hua, Hassan Al-Badawi, Michael C. Stoner, Fateh Entabi, Bryan T. Meriam, Glenn M. LaMuraglia, Michael T. Watkins
Massachusetts General Hospital, Boston, MA

Ischemia reperfusion (IR) is characterized by expression of pro-inflammatory cytokines and cytoprotective growth factors. PJ34, a PARP inhibitor, has been shown to ameliorate inflammation and tissue necrosis in models of stroke and myocardial infarction. This study was designed to evaluate the effects of PJ34 on skeletal muscle cytokine/growth factor levels and tissue viability following IR.
129S1/SVJMJ mice, divided between treated (PJ34) and untreated (UN) groups, were subjected to 3 hours of unilateral hindlimb tourniquet ischemia followed by 4 or 48 hours reperfusion. In the treatment group, PJ34 (15 mg/kg) was given one hour before ischemia and just prior to reperfusion. Mice were sacrificed and muscle harvested from IR and contralateral limbs for measurement of tissue edema (Wet/Dry weight ratio), viability (MTT assay), levels of KC, a potent neutrophil chemoattractant, and VEGF, a cytoprotective growth factor (ELISA).
PJ34 significantly increased skeletal muscle viability after 4 hours reperfusion (p<0.01) and to a greater extent after 48 hours reperfusion (p<0.001) without affecting tissue edema. PJ34 did not alter KC or VEGF levels after 4 hours reperfusion. However, after 48 hours reperfusion, KC levels in PJ34-treated mice were markedly decreased, whereas VEGF levels remained elevated.
(% contralateral)
(pg/mg protein)
(pg/mg protein)
UN-3/4 IR6.0±0.2*43.5±2.133.5±2.8*46.1±3.5*
PJ34-3/4 IR6.4±0.2*51.5±1.5++32.8±5.8*31.0±3.2*
UN-3/48 IR5.8±0.1*62.6±3.773.1±6.0+42.3±3.1*
PJ34-3/48 IR5.9±0.2*100±8**34.0±1.6*40.4±4.4*

*p<0.01 vs. sham; +p<0.001 vs. all groups; ++p<0.01 vs. UN-3/4; **p<0.001 vs. UN-3/48
These data suggest that during early reperfusion, PJ34 modulates tissue injury through pathways independent of KC and VEGF. In contrast, during late reperfusion, PJ34 specifically suppresses the proinflammatory pathway (KC) while preserving the cytoprotective pathway (VEGF).

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