title: Divergent systemic and local inflammatory response to hind limb demand ischemia in wild-type and ApoE-/- mice.
abstract: 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.
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Crawford
authors.forename: Hassan
authors.initials: H
authors.lastname: Albadawi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Robaldo
authors.forename: Michael A
authors.initials: MA
authors.lastname: Peck
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Abularrage
authors.forename: Hyung-Jin
authors.initials: HJ
authors.lastname: Yoo
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Lamuraglia
authors.forename: Michael T
authors.initials: MT
authors.lastname: Watkins
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D054426:Chemokine CXCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism* / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000503:physiopathology*; D012038:Regeneration / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D054426:Chemokine CXCL2; D016207:Cytokines; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A
keywords: Cytokines; Exercise; Growth factors; Inflammation; Ischemia; Reperfusion; Skeletal muscle