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Background: We designed studies to determine whether the ApoE-/- phenotype modulates the local skeletal muscle and systemic inflammatory (plasma) responses to lower extremity demand ischemia. The ApoE-/- phenotype is an experimental model for atherosclerosis in humans., Methods: Aged female ApoE-/- and C57BL6 mice underwent femoral artery ligation, then were divided into sedentary and demand ischemia (exercise) groups on day 14. We assessed baseline and postexercise limb perfusion and hind limb function. On day 14, animals in the demand ischemia group underwent daily treadmill exercise through day 28. Sedentary mice were not exercised. On day 28, we harvested plasma and skeletal muscle from ischemic limbs from sedentary and exercised mice. We assayed muscle for angiogenic and proinflammatory proteins, markers of skeletal muscle regeneration, and evidence of skeletal muscle fiber maturation., Results: Hind limb ischemia was similar in ApoE-/- and C57 mice before the onset of exercise. Under sedentary conditions, plasma vascular endothelial cell growth factor and interleukin-6, but not keratinocyte chemoattractant factor (KC) or macrophage inflammatory protein-2 (MIP-2), were higher in ApoE (P < 0.0001). After exercise, plasma levels of vascular endothelial cell growth factor, KC, and MIP-2, but not IL-6, were lower in ApoE (P < 0.004). The cytokines KC and MIP-2 in muscle were greater in exercised ApoE-/- mice compared with C57BL6 mice (P = 0.01). Increased poly-ADP-ribose activity and mature muscle regeneration were associated with demand ischemia in the C57BL6 mice, compared with the ApoE-/- mice (P = 0.01)., Conclusions: Demand limb ischemia in the ApoE-/- phenotype exacerbated the expression of select systemic cytokines in plasma and blunted indices of muscle regeneration., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: PARP stabilizes DNA and modulates inflammation in murine models of sepsis, stroke, and myocardial infarction. Previous studies have shown that systemic PARP inhibition before hindlimb ischemia preserves tissue viability and modulates cytokine synthesis during reperfusion. The purpose of this study was to determine whether intra-muscular (IM) administration of PJ34, a potent inhibitor of PARP, after the onset of acute hindlimb ischemia (post hoc) modulates the local production of inflammatory mediators during ischemia/reperfusion (I/R)., Materials and Methods: The control tension tourniquet was used to establish unilateral hindlimb ischemia in mice for 3 h followed by 48 h I/R. The treatment group (PJ) received IM PJ34 (10 mg/kg) in the affected hindlimb 90 min into ischemia whereas the control group (UN) received IM saline (150 uL) at the same time point. Skeletal muscle viability (MTT mitochondrial activity), local neutrophil chemoattractant protein (KC), Interleukin 6 (IL-6), Interleukin 1beta (IL-1beta), and Myeloperoxidase (MPO) levels were measured in protein extracts after the reperfusion period., Results: Muscle viability (102% +/- 10 PJ, 78% +/- 4 UN, P = 0.04), IL-B (21.1 +/- 1.3 PJ, 15.5 +/- 1.0 UN, P = 0.02), and IL-6 levels (16.3 +/- 1.2 PJ, 10.9 +/- 1.4 UN, P = 0.04) after 48 I/R were significantly higher in PJ. KC and MPO levels were higher in PJ but neither reached statistical significance., Conclusions: Post hoc PJ34 therapy appears to protect skeletal muscle from I/R injury despite increased levels of local cytokines. These initial findings support the role of local post hoc therapy in the treatment of acute limb threatening ischemia suggesting that further study of this novel therapy is warranted.