TUMOR-NECROSIS-FACTOR ALPHA-INDUCED APOPTOSIS IN CARDIAC MYOCYTES - INVOLVEMENT OF THE SPHINGOLIPID SIGNALING CASCADE IN CARDIAC CELL-DEATH

In the present study, it was shown that physiologically relevant level s of the proinflammatory cytokine TNF alpha induced apoptosis in rat c ardiomyocytes in vitro, as quantified by single cell microgel electrop horesis of nuclei (''cardiac comets'') as well as by morphological and biochemical criteria. It was also shown that TNF alpha stimulated pro duction of the endogenous second messenger, sphingosine, suggesting sp hin-golipid involvement in TNF alpha-mediated cardiomyocte apoptosis. Consistent with this hypothesis, sphingosine strongly induced cardiomy ocyte apoptosis. The ability of the appropriate stimulus to drive card iomyocytes into apoptosis indicated that these cells were primed for a poptosis and were susceptible to clinically relevant apoptotic trigger s, such as TNF alpha. These findings suggest that the elevated TNF alp ha levels seen in a variety of clinical conditions, including sepsis a nd ischemic myocardial disorders, may contribute to TNF alpha-induced cardiac cell death. Cardiamyocyte apoptosis is also discussed in terms of its potential beneficial role in limiting the area of cardiac cell involvement as a consequence of myocardial infarction, viral infectio n! and primary cardiac tumors.