Tumor Necrosis Factor-alpha Contributes to Ischemia- and Reperfusion-Induced Endothelial Activation in Isolated Hearts

During myocardial reperfusion, polymorphonuclear neutrophil (PMN) adhesion involving the intercellular adhesion molecule-1 (ICAM-1) may lead to aggravation and prolongation of reperfusion injury. We studied the role of early tumor necrosis factor-alpha (TNF-alpha) cleavage and nuclear factor-kappa B...

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Bibliographic Details
Published in:Circulation research 1999-03, Vol.84 (4), p.392-400
Main Authors: Kupatt, Christian, Habazettl, Helmut, Goedecke, Axel, Wolf, Dieter A, Zahler, Stefan, Boekstegers, Peter, Kelly, Ralph A, Becker, Bernhard F
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cardiology. Vascular system
Cell Adhesion - physiology
Coronary Circulation - physiology
Coronary heart disease
Endothelium, Vascular - physiopathology
Gene Expression Regulation - physiology
Heart
Hemodynamics - physiology
In Vitro Techniques
Intercellular Adhesion Molecule-1 - genetics
Male
Medical sciences
Myocardial Contraction - physiology
Myocardial Ischemia - physiopathology
Myocardial Reperfusion Injury - physiopathology
Neutrophils - physiology
NF-kappa B - physiology
Rats
RNA, Messenger - metabolism
Transcription Factors - physiology
Tumor Necrosis Factor-alpha - physiology
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Summary:During myocardial reperfusion, polymorphonuclear neutrophil (PMN) adhesion involving the intercellular adhesion molecule-1 (ICAM-1) may lead to aggravation and prolongation of reperfusion injury. We studied the role of early tumor necrosis factor-alpha (TNF-alpha) cleavage and nuclear factor-kappa B (NF-kappa B) activation on ICAM-1 expression and venular adhesion of PMN in isolated hearts after ischemia (15 minutes) and reperfusion (30 to 480 minutes). NF-kappa B activation (electromobility shift assay) was found after 30 minutes of reperfusion and up to 240 minutes. ICAM-1 mRNA, assessed by Northern blot, increased during the same interval. Functional effect of newly synthesized adhesion molecules was found by quantification (in situ fluorescence microscopy) of PMN, given as bolus after ischemia, which became adherent to small coronary venules (10 to 50 [micro sign]m in diameter). After 480 minutes of reperfusion, ICAM-1-dependent PMN adhesion increased 2.5-fold compared with PMN adhesion obtained during acute reperfusion. To study the influence of NF-kappa B on PMN adhesion, we inhibited NF-kappa B activation by transfection of NF-kappa B decoy oligonucleotides into isolated hearts using HIV-liposomes. Decoy NF-kappa B but not control oligonucleotides blocked ICAM-1 upregulation and inhibited the subacute increase in PMN adhesion. Similar effects were obtained using BB 1101 (10 [micro sign]g), an inhibitor of TNF-alpha cleavage enzyme. These data suggest that ischemia and reperfusion in isolated hearts cause liberation of TNF-alpha, activation of NF-kappa B, and upregulation of ICAM-1, an adhesion molecule involved in inflammatory response after ischemia and reperfusion. (Circ Res. 1999;84:392-400.)
ISSN:0009-7330
1524-4571
DOI:10.1161/01.RES.84.4.392