Oxygen radicals trigger activation of NF-kappaB and AP-1 and upregulation of ICAM-1 in reperfused canine heart.
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.
Fan
Haiying
H
Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Sun
Baogui
B
Gu
Qiuping
Q
Lafond-Walker
Anne
A
Cao
Suyi
S
Becker
Lewis C
LC
D000818:Animals; D001783:Blood Flow Velocity; D015152:Blotting, Northern; D003250:Constriction; D003331:Coronary Vessels; D004247:DNA / Q000378:metabolism; D004285:Dogs; D016166:Free Radical Scavengers; D005609:Free Radicals; D005786:Gene Expression Regulation; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006439:Hemodynamics; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D015425:Myocardial Reperfusion; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation
D016166:Free Radical Scavengers; D005609:Free Radicals; C110658:N-(2-mercaptoproprionyl)-glycine; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D018808:Transcription Factor AP-1; D018799:Intercellular Adhesion Molecule-1; D004247:DNA; D009195:Peroxidase; D005998:Glycine