TY - JOUR
T1 - Hydrogen peroxide induces tumor necrosis factor α-mediated cardiac injury by a P38 mitogen-activated protein kinase-dependent mechanism
AU - Meldrum, D. R.
AU - Dinarello, C. A.
AU - Cleveland, Jr
AU - Cain, B. S.
AU - Shames, B. D.
AU - Meng, X.
AU - Harken, A. H.
AU - Zwischenberger, J. B.
AU - Billiar, T. R.
PY - 1998
Y1 - 1998
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0031877074&partnerID=8YFLogxK
U2 - 10.1016/S0039-6060(98)70133-3
DO - 10.1016/S0039-6060(98)70133-3
M3 - Article
C2 - 9706151
AN - SCOPUS:0031877074
SN - 0039-6060
VL - 124
SP - 291
EP - 297
JO - Surgery
JF - Surgery
IS - 2
ER -