Tumor necrosis factor-α provokes a hypertrophic growth response in adult cardiac myocytes

Background: Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine with a broad range of concentration-dependent effects. The recent observation that TNF-α is expressed by the cardiac myocyte after certain forms of stress suggests that TNF-α might contribute to the maintenance of normal tissue homeostasis after environmental injury. Accordingly, the purpose of this study was to examine the effects of TNF-α on protein synthesis in cultured adult cardiac myocytes. Methods and Results: Cultured adult feline cardiac myocytes were stimulated with 10 to 1000 U/mL TNF-α to examine the effects of this cytokine on the rate of protein synthesis and degradation. Stimulation with TNF-α led to an accelerated rate of general protein synthesis and a time-dependent decrease in protein degradation in adult cardiac myocytes. The specificity of these findings was demonstrated by studies in which the effects of TNF-α on protein synthesis were blocked by a neutralizing anti-TNF-α antibody as well as studies in which TNF-α- conditioned medium had no effect on protein synthesis in myocytes. In addition to the TNF-α induced increase in the general protein synthesis, stimulation with TNF-α led to a 2.4-fold increase in net actin protein synthesis and a 3.3-fold increase in net myosin heavy chain synthesis. Finally, the effects of TNF-α on adult cardiac myocytes were shown to be dependent on cell-substrate interaction, suggesting that the cell signaling pathways used by TNF-α are dependent on a preserved interaction between cell integrins and the extracellular matrix. Conclusions: The observation that TNF-α provokes a hypertrophic growth response in cardiac myocytes suggests that TNF-α may play an important role in myocardial homeostasis after environmental stress.