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 m yocardial dysfunction and cardiomyocyte death; however, mechanisms res ponsible remain unknown. We hypothesized that hydrogen peroxide (H2O2) induces myocardial dysfunction and cardiomyocyte death via P38 mitoge n-activated protein kinase (MAPK)-mediated myocardial tumor necrosis f actor (TNF) production. Methods. Langendorff perfused rat hearts (6/gr oup) were subjected to oxidant stress (H2O2 infusion; 300 mmol/L x 80 minutes), with and without prior infusion of a specific P38 kinase MAP K inhibitor (P38i = 1 mmol/L/min x 5 minutes) or TNF neutralization (2 0 mg TNF binding protein (BP)/min x 80 minutes). Developed pressure (D P), coronary flow, and end-diastolic pressure were continuously record ed. Myocardial creatine kinase (CK) loss was measured in the coronary effluent, and tissue TNF was measured in myocardial homogenates. Resul ts. Eighty minutes of H2O2 infusion induced a 6.5-fold increase in myo cardial TNF production which was associated with a 70% decrease in DP and increase in CK loss. P38 MAPK inhibition or TNF-BP decreased myoca rdia; TNF production, cardiomyocyte death, and myocardial dysfunction. Conclusions. These results demonstrate that H2O2 alone induces myocar dial TNF production. P38 MAPK is an oxidant-sensitive enzyme that medi ates oxidant-induced myocardial TNF production, cardiac dysfunction, a nd cardiomyocyte death.