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

The transcription factor NF-kappaB regulates expression of genes that are involved in inflammation, immune response, viral infection, cell survival, and division. However. the role of NF-kappaB in hypertrophic: growth of terminally differentiated cardiomyocytes is unknown. Here we report that NF-kappaB activation is required for hypertrophic growth of cardiomyocytes. In cultured rat primary neonatal ventricular cardiomyocytes, the nuclear translocation of NF-kappaB and its transcriptional activity were stimulated by several hypertrophic agonists, including phenylephrine. endothelin-1, and angiotensin II. The activation of NF-kappaB was inhibited by expression of a "supersuppressor" I kappaB alpha mutant that is resistant to stimulation-induced degradation and a dominant negative I kappaB kinase (IKK beta) mutant that can no longer be activated by phosphorylation. Furthermore, treatment with phenylephrine induced I kappaB alpha degradation in an IKK-dependent manner, suggesting that NF-kappaB is a downstream target of the hypertrophic agonists. Importantly, expression of the supersuppressor I kappaB alpha mutant or the dominant negative IKK beta mutant blocked the hypertrophic agonist-induced expression of the embryonic gene atrial natriuretic factor and enlargement of cardiomyocytes. Conversely, overexpression of NF-kappaB itself induced atrial natriuretic factor expression and cardiomyocyte enlargement. These findings suggest that NF-kappaB plays a critical role in the hypertrophic growth of cardiomyocytes and may serve as a potential target for the intervention of heart disease.