Hydrogen peroxide induces tumor necrosis factor alpha-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 MPAK is an oxidant-sensitive enzyme that mediates oxidant-induced myocardial TNF production, cardiac dysfunction, and cardiomyocyte death.
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
D R
DR
Meldrum
C A
CA
Dinarello
J C
JC
Cleveland
B S
BS
Cain
B D
BD
Shames
X
X
Meng
A H
AH
Harken
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003402:Creatine Kinase / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016277:Ventricular Function, Left; D048051:p38 Mitogen-Activated Protein Kinases
D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003402:Creatine Kinase