Activation of NF-κB is Required for Hypertrophic Growth of Primary Rat Neonatal Ventricular Cardiomyocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-06, Vol.98 (12), p.6668-6673
• Main Authors: Purcell, Nicole H., Tang, Guilin, Yu, Chenfei, Mercurio, Frank, DiDonato, Joseph A., Lin, Anning
• Format: Article
• Language: English
• Subjects: Agonists; Angiotensin II - pharmacology; Animals; Animals, Newborn; Atrial Natriuretic Factor - genetics; Biological Sciences; Cardiomegaly - etiology; cardiomyocytes; Cell growth; Cells, Cultured; DNA-Binding Proteins - metabolism; Epithelial cells; Gene expression regulation; Genetic vectors; Hypertrophy; I-kappa B Proteins; Myocardium; NF-kappa B - physiology; NF-KappaB Inhibitor alpha; phenylephrine; Phenylephrine - pharmacology; Plasmids; Rats; Rats, Sprague-Dawley; Reporter genes; Surface areas
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.111155798

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