Tumor Necrosis Factor-α Provokes a Hypertrophic Growth Response in Adult Cardiac Myocytes

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine with a broad range of concentration-dependent effects. The recent observation that TNF-alpha is expressed by the cardiac myocyte after certain forms of stress suggests that TNF-alpha 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-alpha 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-alpha to examine the effects of this cytokine on the rate of protein synthesis and degradation. Stimulation with TNF-alpha 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-alpha on protein synthesis were blocked by a neutralizing anti-TNF-alpha antibody as well as studies in which TNF-alpha-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 net actin protein synthesis and a 3.3-fold increase in net myosin heavy chain synthesis. Finally, the effects of TNF-alpha on adult cardiac myocytes were shown to be dependent on cell-substrate interaction, suggesting that the cell signaling pathways used by TNF-alpha are dependent on a preserved interaction between cell integrins and the extracellular matrix. CONCLUSIONS: The observation that TNF-alpha provokes a hypertrophic growth response in cardiac myocytes suggests that TNF-alpha may play an important role in myocardial homeostasis after environmental stress.