Smad7 Is Induced by Norepinephrine and Protects Rat Hepatocytes from Activin A-induced Growth Inhibition

Abstract

Activin A induces growth arrest of rat hepatocytes in vitro and in vivo. The α1-adrenergic agonist, norepinephrine (NE), enhances epidermal growth factor-stimulated DNA synthesis and inhibits activin A-induced growth inhibition, but the mechanisms of these actions are unclear. Smad proteins have recently been identified as intracellular signaling mediators of transforming growth factor-β family members. In the present study, we explored how NE modulates the Smad signaling pathway in rat cultured hepatocytes. We demonstrate that NE inhibits activin A-induced nuclear accumulation of Smad2/3 and that NE rapidly induces inhibitory Smad7 mRNA expression. Infection of Smad7 adenovirus into rat hepatocytes inhibited activin A-induced nuclear accumulation of Smad2/3, enhanced epidermal growth factor-stimulated DNA synthesis, and abolished the growth inhibitory effect of activin A. We also demonstrated that the induction of Smad7 by NE is dependent on nuclear factor-κB (NF-κB). The amount of active NF-κB complex rapidly increased after NE treatment. Preincubation of the cells with an NF-κB pathway inhibitor N-tosyl-L-phenylalanine chloromethyl ketone or infection of the cells with an adenovirus expressing an IκB super-repressor (Ad5IκB) abolished the NE-induced Smad7 expression. These results indicate a mechanism of transmodulation between the Smad and trimeric G protein signaling pathways in rat hepatocytes.