β1‐adrenergic receptor‐mediated transactivation of epidermal growth factor receptor acutely regulates cardiac gene expression

Abstract

β1‐adrenergic receptor (β1AR)‐mediated transactivation of epidermal growth factor receptor (EGFR) has been shown provide cardioprotection. While the mechanisms responsible for this effect are unknown, we hypothesized that β1AR‐mediated EGFR transactivation could modulate cardiac gene expression. To test this hypothesis, C57BL/6 mice were treated with isoproterenol (ISO) in the presence or absence of an EGFR antagonist (Gefitinib or AG1478). Following 10 minutes of stimulation, phosphorylation of ERK1/2 and Akt were each shown to be increased in response to ISO, and significantly ablated in the presence of AG 1478. Assessment of the subcellular localization of phosphorylated ERK1/2 and Akt in rat neonatal cardiomyocytes in response to β1AR‐mediated EFGR transactivation revealed significant increases in the nucleus, which were ablated by EGFR inhibition. To determine the impact of β1AR‐mediated EGFR transactivation on acute gene expression responses in the heart, mice were treated for 1 hour as described above and real‐time PCR was performed on a panel of EGFR‐regulated pro‐ or anti‐apoptotic genes. Of these, Bcl2l11 expression increased significantly in response to ISO and was attenuated with the addition of gefitinib. Altogether, these results reveal that β1AR‐mediated EGFR transactivation induces differential ERK1/2 and Akt targeting and selective regulation of cardiac gene expression. Funding was provided by the National Institutes of Health (HL‐105414 to DGT).