Divergent systemic and local inflammatory response to hind limb demand ischemia in wild-type and ApoE–/– mice

Abstract

Introduction Studies were designed 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 divided into sedentary and demand ischemia (exercise) groups on day 14. Baseline and post exercise limb perfusion and hind limb function were assessed. On day 14, animals in the demand ischemia group underwent daily treadmill exercise through day 28. Sedentary mice were not exercised. On day 28, plasma and skeletal muscle from ischemic limbs were harvested from sedentary and exercised mice. Muscle was assayed for angiogenic and pro-inflammatory proteins, markers of skeletal muscle regeneration, and evidence of skeletal muscle fiber maturation. Results Hind limb ischemia was similar in ApoE −/− and C57 mice prior to the onset of exercise. Under sedentary conditions, plasma VEGF, IL-6, but not KC or MIP-2 were higher in ApoE (P<0.0001). Following exercise, plasma levels of VEGF, KC and MIP-2, but not IL-6 were lower in ApoE (P<0.004). The cytokines KC and MIP-2 in muscle was greater in exercised ApoE−/− mice as compared to C57BL6 mice (p=0.01). Increased PAR activity, and mature muscle regeneration was associated with demand ischemia in the C57BL6 mice as compared to the ApoE −/− mice (p=0.01). Conclusion Demand limb ischemia in the ApoE−/− phenotype exacerbated the expression of select systemic cytokines in plasma and blunted indices of muscle regeneration.

Effect of limb demand ischemia on autophagy and morphology in mice

“…Age-matched C57BL6 male mice were acquired from Jackson Laboratory (Bar Harbor, ME) after being fed a diet consisting of 60% kcal from fat for 26 weeks to induce obesity, insulin resistance, and diabetes 16 . To induce hind limb ischemia, all mice were subjected to unilateral femoral artery ligation surgery (FAL) in one hind limb or sham surgery in the contralateral hind limb and then were allowed to recover for two weeks as previously described 17, 18 . Subsequently, the mice were divided into two groups; exercise group and sedentary group.…”

Protective Effect of Edaravone Against Oxidative Stress in C2C12 Myoblast and Impairment of Skeletal Muscle Regeneration Exposed to Ischemic Injury in Ob/ob Mice

“…Under deep anesthesia, the right femoral artery was exposed and ligated at a level between epigastric artery and bifurcation of saphena and popliteal artery (Crawford et al, 2013). Furthermore, 3 mg/kg edaravone or saline solution was injected intraperitoneally 30 min before the femoral artery ligation.…”

Crossroads between peripheral atherosclerosis, western-type diet and skeletal muscle pathophysiology: emphasis on apolipoprotein E deficiency and peripheral arterial disease

“…In this regard, a few studies have used ApoE -/- mice as a model for PAD by inducing limb ischemia via femoral artery ligation [ 211 , 214 , 215 ]. Specifically, ApoE -/- mice subjected to ischemia followed by exercise have similar hyperaemic response with exercising PAD patients and exhibit delayed regeneration and increased inflammation [ 214 , 215 ]. In a recent study ApoE -/- mice on a western-type diet and subsequent induced-ischemia, display impaired ambulation compared to wild type mice due to delayed restoration of blood perfusion [ 216 ].…”