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

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.