Oxygen radicals trigger activation of NF-kappaB and AP-1 and upregulation of ICAM-1 in reperfused canine heart

Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1778-86. doi: 10.1152/ajpheart.00796.2000.

Abstract

We investigated whether oxygen radicals generated during ischemia-reperfusion trigger postischemic inflammation in the heart. Closed-chest dogs underwent 90-min coronary artery occlusion, followed by 1- or 3-h reperfusion: 10 dogs received the cell-permeant oxygen radical scavenger N-(2-mercaptopropionyl)-glycine (MPG; 8 mg x kg(-1) x h(-1) intracoronary) beginning 5 min before reperfusion, and 9 dogs received vehicle. Blood flow (microspheres), intercellular adhesion molecule (ICAM)-1 protein expression (immunohistochemistry), ICAM-1 gene activation (Northern blotting), nuclear DNA binding activity of nuclear factor (NF)-kappaB and AP-1 (electrophoretic mobility shift assays), and neutrophil (PMN) accumulation (myeloperoxidase activity) were assessed in myocardial tissue samples. ICAM-1 protein expression was high in vascular endothelium after ischemia-reperfusion but was markedly reduced by MPG. MPG treatment also markedly decreased expression of ICAM-1 mRNA and tissue PMN accumulation. Nuclear DNA binding activities of NF-kappaB and AP-1, increased by ischemia-reperfusion, were both markedly decreased by MPG at 1 h of reperfusion. However, by 3 h, AP-1 activity was only modestly reduced by MPG and NF-kappaB activity was not significantly different from ischemic-reperfused controls. These results suggest that oxygen radicals generated in vivo during reperfusion trigger early activation of NF-kappaB and AP-1, resulting in upregulation of the ICAM-1 gene in vascular endothelium and subsequent tissue accumulation of activated PMNs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Flow Velocity
  • Blotting, Northern
  • Constriction
  • Coronary Vessels
  • DNA / metabolism
  • Dogs
  • Free Radical Scavengers
  • Free Radicals
  • Gene Expression Regulation
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Hemodynamics
  • Immunohistochemistry
  • Intercellular Adhesion Molecule-1 / analysis
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Myocardial Ischemia / metabolism*
  • Myocardial Ischemia / pathology
  • Myocardial Reperfusion*
  • NF-kappa B / metabolism*
  • Neutrophils / pathology
  • Neutrophils / physiology
  • Peroxidase / metabolism
  • RNA, Messenger / analysis
  • Reactive Oxygen Species / pharmacology*
  • Sulfhydryl Compounds / pharmacology
  • Transcription Factor AP-1 / metabolism*
  • Transcriptional Activation

Substances

  • Free Radical Scavengers
  • Free Radicals
  • N-(2-mercaptoproprionyl)-glycine
  • NF-kappa B
  • RNA, Messenger
  • Reactive Oxygen Species
  • Sulfhydryl Compounds
  • Transcription Factor AP-1
  • Intercellular Adhesion Molecule-1
  • DNA
  • Peroxidase
  • Glycine