The protective effects of tumor necrosis factor receptor 1 deletion on hindlimb ischemia

( views:114, downloads:0 )
Author:
JIANG Jun()
LI Changling()
WEI Ling()
WANG Jian'an()
Journal Title:
CHINESE JOURNAL OF EMERGENCY MEDICINE
Issue:
Volume 15, Issue 03, 2006
DOI:
Key Word:
Tumor necrosis factor α receptor 1;Hindlimb ischemia;Apoptosis

Abstract: Objective Signals in the tumor necrosis factor α TNFα pathway, including TNFα and tumor necrosis factor α receptor 1TNFR1, are upregulated after acute hindlimh ischemia. It is unclear, however, whether this upregulation is apathophysiological consequence or a compensatory response. In the present study, the effect of TNFR1 deletion in a mouse model of hindlimb ischemia was investigated.Methods Hindlimb ischemia was produced through ligation of the proximal and distal left femoral artery and its branches in TNFR1 knockout TNFR1-/- and wild type WT mice. Laser Doppler blood flow measurement showed that limb perfusion was significantly higher in TNFR1-/- mice than that in the WT mice at 1 day after operation.Results The calculated ischemic scores were 3.67 ± 0.52 in WT group and 1.83 ± 0.41 in TNFR1-/- group P <0.05. The rate of amputation was 50% in WT mice versus 0% in TNFR1-/- mice. There were less TUNEL positive cells in the calf muscle of TNFR1-/- mice than that of WT mice. Furthermore, DNA fragmentation was more obvious in WT mice.Western blot showed less expression of Bax and cleaved caspase 3 in TNFR1-/- mice 1 day after ischemia, suggesting a reduced apoptotic process in the absence of TNFR1.Conclusion In mice with hindlimb ischemia, knockout of TNFR1 prevents the activation of death-related proteins down streaming to TNF α and attenuated cell death including apoptosis. Systemic block of the TNFR1 might be a new interventional methods-to preserve the limbs from acute ischemic attack in patients with peripheral arterial obstructive disease.

  • [1]Giannini D,Balbarini A.Thrombolytic therapy in peripheral arterial disease.Curr Drug Targets Cardiovasc Haematol Disord,2004,4(3):249-258.
  • [2]Imao M,Nagaki M,Imose M,et al.Differential caspase-9-dependent signaling pathway between tumor necrosis factor receptor-and Fas-mediated hepatocyte apoptosis in mice.Liver Int,2006,26 (1):137-146.
  • [3]Park H,Park SG,Kim J,et al.Signaling pathways for TNF production induced by human aminoacyl-tRNA synthetase-associating factor,p43.Cytokine,2002,20 (4):148-153.
  • [4]Tuomisto TT,Rissanen TT,Vajanto I,et al.HIF-VEGF-VEGFR-2,TNF-alpha and IGF pathways are upregulated in critical human skeletal muscle ischemia as studied with DNA array.Atherosclerosis,2004,174 (1):111-120.
  • [5]Hoff DA,Gregersen H,Odegaard S,et al.A multimodal laser Doppler and endosonographic distension device for studying mechanosensation and mucosal blood flow in the oesophagus.Neurogastroenterol Motil,2006,18 (3):243-248.
  • [6]Zhang XD,Wu JJ,Gillespie S,et al.Human Melanoma Cells Selected for Resistance to Apoptosis by Prolonged Exposure to Tumor Necrosis Factor-Related Apoptosis-inducing Ligand Are More Vulnerable to Necrotic Cell Death Induced by Cisplatin.Clin Cancer Res,2006,12 (4):1355-1364.
  • [7]Aslan M,Yucel I,Akar Y,et al.Nitrotyrosine formation and apoptosis in rat models of ocular injury.Free Radic Res,2006,40(2):147-153.
  • [8]Aronow WS.Management of peripheral arterial disease.Cardiol Rev2005,13 (2):61-68.
  • [9]Baumgartner I,Schainfeld R,Graziani L.Management of peripheral vascular disease.Annu Rev Med,2005,56:249-272.
  • [10]Aggarwal BB,Shishodia S,Ashikawa K,et al.The role of TNF and its family members in inflammation and cancer:lessons from gene deletion.Curr Drug Targets Inflamm Allergy,2002,1 (4):327-341.
  • [11]Retter AS,Frishman WH.The role of tumor necrosis factor in cardiac disease.Heart Dis,2001,3 (5):319-325.
  • [12]Sun M,Dawood F,Wen WH,et al.Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction.Circulation,2004,110(20):3221-3228.
  • [13]Whittall T,Wang Y,Kelly CG,et al.Tumour necrosis factor-alpha production stimulated by heat shock protein 70 and its inhibition in circulating dendritic cells and cells eluted from mucosal tissues in Crohn's disease.Clin Exp Immunol,2006,143 (3):550-559.
  • [14]Muller-Ehmsen J,Schwinger RH.TNF and congestive heart failure:therapeutic possibilities.Expert Opin Ther Targets,2004,8 (3):203-209.
  • [15]Higuchi Y,McTiernan CF,Frye CB,et al.Tumor necrosis factor receptors 1 and 2 differentially regulate survival,cardiac dysfunction,and remodeling in transgenic mice with tumor necrosis factor-alphainduced cardiomyopathy.Circulation,2004,109 (15):1892-1897.
  • [16]Wang J,Wang H,Zhang Y,et al.Impairment of HERG K (+) channel function by tumor necrosis factor-alpha:role of reactive oxygen species as a mediator.J Biol Chem,2004,279(14):13289-13292.
WanfangData CO.,Ltd All Rights Reserved
About WanfangData | Contact US
Healthcare Department, Fuxing Road NO.15, Haidian District Beijing, 100038 P.R.China
Tel:+86-010-58882616 Fax:+86-010-58882615 Email:yiyao@wanfangdata.com.cn