Hydrogen peroxide induces tumor necrosis factor α-mediated cardiac injury by a P38 mitogen-activated protein kinase-dependent mechanism

D. R. Meldrum, C. A. Dinarello, Jr Cleveland, B. S. Cain, B. D. Shames, X. Meng, A. H. Harken, J. B. Zwischenberger, T. R. Billiar

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Background. Oxidant stress caused by ischemia or endotoxemia induces myocardial dysfunction and cardiomyocyte death; however, mechanisms responsible remain unknown. We hypothesized that hydrogen peroxide (H2O2) induces myocardial dysfunction and cardiomyocyte death via P38 mitogen- activated protein kinase (MAPK)-mediated myocardial tumor necrosis factor (TNF) production. Methods. Langendorff perfused rat hearts (6/group) were subjected tO oxidant stress (H2O2 infusion; 300 mmol/L x 80 minutes), with and without prior infusion of a specific P38 kinase MAPK inhibitor (P38i =1 mmol/L/min x 5 minutes) or TNF neutralization (20 mg TNF binding protein (BP)/min x 80 minutes). Developed pressure (DP), coronary flow, and end- diastolic pressure were continuously recorded. Myocardial creatine kinase (CK) loss was measured in the coronary effluent, and tissue TNF was measured in myocardial homogenates. Results. Eighty minutes of H2O2 infusion induced a 6.5-fold increase in myocardial TNF production, which was associated with a 70% decrease in DP and increase in CK loss. P38 MAPK inhibition or TNF-BP decreased myocardial TNF production, cardiomyocyte death, and myocardial dysfunction. Conclusions. These results demonstrate that H2O2 alone induces myocardial TNF production P38 MAPK is an oxidant-sensitive enzyme that mediates oxidant-induced myocardial TNF production, cardiac dysfunction, and cardiomyocyte death.

Original languageEnglish
Pages (from-to)291-297
Number of pages7
JournalSurgery
Volume124
Issue number2
DOIs
StatePublished - 1998

ASJC Scopus subject areas

  • Surgery

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