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

• Published in: Surgery 1998-08, Vol.124 (2), p.291-297
• Main Authors: Meldrum, Daniel R., Dinarello, Charles A., Cleveland, Joseph C., Cain, Brian S., Shames, Brian D., Meng, Xianzhong, Harken, Alden H.
• Format: Article
• Language: English
• Subjects: Animals; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Creatine Kinase - metabolism; Enzyme Activation - drug effects; Heart Diseases - chemically induced; Heart Diseases - metabolism; Hydrogen Peroxide - pharmacology; Male; Mitogen-Activated Protein Kinases; Myocardium - chemistry; Myocardium - enzymology; Oxidants - pharmacology; Oxidative Stress - physiology; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha - metabolism; Ventricular Function, Left
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/S0039-6060(98)70133-3

Background: Oxidant stress caused by ischemia or endotoxemia induces myocardial dysfunction and cardiomyocyte death; however, mechanisms responsible remain unknown. We hypothesized that hydrogen peroxide (H 2O 2) 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 (H 2O 2 infusion; 300 mmol/L × 80 minutes), with and without prior infusion of a specific P38 kinase MAPK inhibitor (P38i = 1 mmol/L/min × 5 minutes) or TNF neutralization (20 mg TNF binding protein (BP)/min × 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 H 2O 2 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 H 2O 2 alone induces myocardial TNF production. P38 MAPK is an oxidant-sensitive enzyme that mediates oxidant-induced myocardial TNF production, cardiac dysfunction, and cardiomyocyte death. (Surgery 1998;124:291-7.)