title: Role of tumor necrosis factor-alpha in myocardial dysfunction and apoptosis during hindlimb ischemia and reperfusion.
abstract: OBJECTIVE
  Peripheral vascular surgery involving limb ischemia/reperfusion is associated with tumor necrosis factor-alpha production and an increased risk of cardiac complications. The objective of this study was to investigate the role of tumor necrosis factor-alpha in myocardial apoptosis and dysfunction following hindlimb ischemia/reperfusion.
  
  
  METHODS
  Randomized perspective animal study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Adults male tumor necrosis factor-alpha(-/-) and littermate wild-type mice.
  
  
  METHODS
  Bilateral hindlimb ischemia/reperfusion was induced in wild-type and tumor necrosis factor-alpha(-/-) mice using tourniquet occlusion. After 2 hrs of hindlimb ischemia, the tourniquets were released, allowing reperfusion for 0.5-24 hrs.
  
  
  RESULTS
  In wild-type mice, hindlimb ischemia/reperfusion resulted in myocardial depression early during the reperfusion period (p < .05). These effects were temporally correlated with enhanced levels of myocardial and plasma tumor necrosis factor-alpha. All variables were restored to baseline levels by 24 hrs of reperfusion. Myocardial apoptosis, assessed by cell death enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling staining, and caspase-3 activity, was also significantly higher at 6 hrs of reperfusion (p < .05) but returned to baseline levels by 24 hrs. Interestingly, cardiac dysfunction and myocardial apoptosis were abolished in tumor necrosis factor-alpha mice subjected to the same degree of hindlimb ischemia/reperfusion as the wild-type mice. Treatment of etanercept restored cardiac function in wild-type mice.
  
  
  CONCLUSIONS
  Tumor necrosis factor-alpha contributes significantly to myocardial dysfunction and apoptosis in hindlimb ischemia/reperfusion. Although a causal link between myocardial apoptosis and cardiac dysfunction is not established, our study does suggest that tumor necrosis factor-alpha may be a potential therapeutic target for cardiac injury in clinical situations involving prolonged remote ischemia/reperfusion.
authors.affiliation: Cardiology Research Lab, Centre for Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, Victoria Hospital, Ontario, Canada.
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.forename: Joel A
authors.initials: JA
authors.lastname: Hamilton
authors.forename: Ji
authors.initials: J
authors.lastname: Shen
authors.forename: Theresa
authors.initials: T
authors.lastname: Pang
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Jones
authors.forename: Richard F
authors.initials: RF
authors.lastname: Potter
authors.forename: J Malcolm O
authors.initials: JM
authors.lastname: Arnold
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001794:Blood Pressure; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D006339:Heart Rate; D006614:Hindlimb / Q000098:blood supply*; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000150:complications*; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases