TUMOR-NECROSIS-FACTOR-ALPHA PROVOKES A HYPERTROPHIC GROWTH-RESPONSE IN ADULT CARDIAC MYOCYTES

Background Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cy tokine with a broad range of concentration-dependent effects. The rece nt observation that TNF-alpha is expressed by the cardiac myocyte afte r certain forms of stress suggests that TNF-alpha might contribute to the maintenance of normal tissue homeostasis after environmental injur y. Accordingly, the purpose of this study was to examine the effects o f TNF-alpha on protein synthesis in cultured adult cardiac myocytes. M ethods and Results Cultured adult feline cardiac myocytes were stimula ted with 10 to 1000 U/mL TNF-alpha to examine the effects of this cyto kine on the rate of protein synthesis and degradation. Stimulation wit h TNF-alpha led to an accelerated rate of general protein synthesis an d a time-dependent decrease in protein degradation in adult cardiac my ocytes. The specificity of these findings was demonstrated by studies in which the effects of TNF-alpha on protein synthesis were blocked by a neutralizing anti-TNF-alpha antibody as well as studies in which TN F-Lu-conditioned medium had no effect on protein synthesis in myocytes . In addition to the TNF-alpha-induced increase in the general protein synthesis, stimulation with TNF-alpha led to a 2.4-fold increase in n et actin protein synthesis and a 3.3-fold increase in net myosin heavy chain synthesis. Finally, the effects of TNF-alpha on adult cardiac m yocytes were shown to be dependent on cell-substrate interaction, sugg esting that the cell signaling pathways used by TNF-alpha are dependen t on a preserved interaction between cell integrins and the extracellu lar matrix. Conclusions The observation that TNF-alpha provokes a hype rtrophic growth response in cardiac myocytes suggests that TNF-alpha m ay play an important role in myocardial homeostasis after environmenta l stress.