Activation of NF-kappa B is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes

The transcription factor NF-kappaB regulates expression of genes that are i nvolved in inflammation, immune response, viral infection, cell survival, a nd division. However. the role of NF-kappaB in hypertrophic: growth of term inally differentiated cardiomyocytes is unknown. Here we report that NF-kap paB activation is required for hypertrophic growth of cardiomyocytes. In cu ltured rat primary neonatal ventricular cardiomyocytes, the nuclear translo cation of NF-kappaB and its transcriptional activity were stimulated by sev eral hypertrophic agonists, including phenylephrine. endothelin-1, and angi otensin II. The activation of NF-kappaB was inhibited by expression of a "s upersuppressor" I kappaB alpha mutant that is resistant to stimulation-indu ced degradation and a dominant negative I kappaB kinase (IKK beta) mutant t hat can no longer be activated by phosphorylation. Furthermore, treatment w ith phenylephrine induced I kappaB alpha degradation in an IKK-dependent ma nner, suggesting that NF-kappaB is a downstream target of the hypertrophic agonists. Importantly, expression of the supersuppressor I kappaB alpha mut ant or the dominant negative IKK beta mutant blocked the hypertrophic agoni st-induced expression of the embryonic gene atrial natriuretic factor and e nlargement of cardiomyocytes. Conversely, overexpression of NF-kappaB itsel f induced atrial natriuretic factor expression and cardiomyocyte enlargemen t. These findings suggest that NF-kappaB plays a critical role in the hyper trophic growth of cardiomyocytes and may serve as a potential target for th e intervention of heart disease.