A20 is dynamically regulated in the heart and inhibits the hypertrophic response

Background-Nuclear factor (NF)-kappaB signaling has been implicated in cardiomyocyte hypertrophy. Here, we determine the cardiac regulation and biological activity of A20, an inhibitor of NF-kappaB signaling. Methods and Results-Mice were subjected to aortic banding, and A20 expression was examined. A20 mRNA upregulation (4.3 +/- 1.5- fold; P < 0.05) was detected 3 hours after banding, coinciding with peak NF-κB activation. A20 was also upregulated in cultured neonatal cardiomyocytes stimulated with phenylephrine or endothelin-1 (2.8 ± 0.6- and 4 ± 1.1-fold, respectively; P < 0.05), again paralleling NF-kappaB activation. Infection of cardiomyocytes with an adenoviral vector ( Ad) encoding A20 inhibited tumor necrosis factor-alpha-stimulated NF-kappaB signaling with an efficacy comparable to dominant negative inhibitor of kappa-B kinase beta (dnIKKbeta). Ad.dnIKKbeta-infected cardiomyocytes exhibited increased apoptosis when they were serum starved or subjected to hypoxia-reoxygenation, whereas Ad. A20-infected cardiomyocytes did not. Expression of Ad. A20 inhibited the hypertrophic response in cardiomyocytes stimulated with phenylephrine or endothelin-1. Conclusions-A20 is dynamically regulated during acute biomechanical stress in the heart and functions to attenuate cardiac hypertrophy through the inhibition of NF-kappaB signaling without sensitizing cardiomyocytes to apoptotic cell death.