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

Abstract

Background - Nuclear factor (NF)-kB signaling has been implicated in cardiomyocyte hypertrophy. Here, we determine the cardiac regulation and biological activity of A20, an inhibitor of NF-kB 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-kB 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-kB activation. Infection of cardiomyocytes with an adenoviral vector (Ad) encoding A20 inhibited tumor necrosis factor-?-stimulated NF-kB signaling with an efficacy comparable to dominant negative inhibitor of k-B kinase ? (dnIKK?). Ad.dnIKK?-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-kB signaling without sensitizing cardiomyocytes to apoptotic cell death.