© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Release of TNF-
during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers
aDepartment of Physiology, University of Munich, Schillerstr. 44, 80336 Munich, Germany
bDepartment of Anatomy, University of Munich, Munich, Germany
cDepartment of Clinical Biochemistry, University of Munich, Munich, Germany
*Corresponding author. Tel.: +49-89-5996-380; fax: +49-89-5996-378. Email address: B.F.Becker{at}LRZ.UNI-MUENCHEN.DE
Objectives: Our study sought to elucidate the role of oxidative stress for shedding of tumor necrosis factor-
(TNF-) and for activating TNF--converting enzyme (TACE). Background: TNF-, a central inflammatory cytokine, is discussed as one of the mediators of reperfusion injury. Shedding of membrane-bound pro-TNF- is thought to be largely due to TNF--converting enzyme (TACE). Methods: Release of TNF- and TACE dependency were studied in isolated rat hearts and in the human mast cell line HMC-1. Results: In reperfused hearts, interstitial release of TNF- occurred in two phases (2–10 and >45 min). It depended on the presence of oxygen during reperfusion and was attenuated by reduced glutathione. Infusion of the oxidants H2O2 or HOCl elicited release in non-ischemic hearts. TNF- release was inhibited in hearts treated with degranulation inhibitors ketotifen or cromoglycate, suggesting mast cells as major source for myocardial TNF-. This was confirmed by tissue staining. Post-ischemic release of histamine, however, did not parallel that of TNF-. Heart tissue contained mainly mature TACE. HMC-1 expressed abundant pro-TACE and cleaved the pro-TNF--peptide Ac-SPLAQAVRSSSR-NH2. However, cleavage was nonspecific and only partly inhibited by TACE inhibitor TAPI-2 (10–100 µmol/l), while it was stimulated by H2O2 and HOCl and fully blocked by the nonspecific metalloprotease inhibitor o-phenanthroline. Conclusions: The mechanism underlying TNF- release from post-ischemic myocardium is oxidation-dependent but largely independent of activation of TACE. Mast cell stabilizers may be useful in preventing TNF- release during reperfusion.
KEYWORDS Cytokines; Free radicals; Ischemia; Reperfusion
Abbreviations: TNF-, tumor necrosis factor- • TACE, TNF--converting enzyme • ADAM, a disintegrin and metalloproteinase • MMP, matrix metalloproteinase • TAPI-2, TNF- protease inhibitor: HONHCOCH2CH(CH2CH(CH3)2CO-t-Butyl-Gly-Ala-NHCH2CH2NH2 • KHB, Krebs–Henseleit buffer • GSH, reduced glutathione • HMC-1, human mast cell line-1 • CABG, coronary artery bypass grafting • DSCG, disodium cromoglycate
* Supported by SFB 469 of the German Research Council (DFG), Bonn, Germany.
Time for primary review 25 days
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