Chronic stimulation of β-
adrenergic receptors (βAR) can promote survival signaling via transactivation of
epidermal growth factor receptor (EGFR) but ultimately alters cardiac structure and contractility over time, in part via enhanced
cytokine signaling. We hypothesized that chronic
catecholamine signaling will have a temporal impact on cardiac transcript expression in vivo, in particular
cytokines, and that EGFR transactivation plays a role in this process. C57BL/6 mice underwent infusion with vehicle or
isoproterenol (Iso)±gefitinib (Gef) for 1 or 2 wk. Cardiac contractility decreased following 2 wk of Iso treatment, while
cardiac hypertrophy,
fibrosis, and apoptosis were enhanced at both timepoints. Inclusion of Gef preserved contractility, blocked Iso-induced apoptosis, and prevented
hypertrophy at the 2-wk timepoint, but caused
fibrosis on its own. RNAseq analysis revealed hundreds of cardiac transcripts altered by Iso at each timepoint with subsequent RT-quantitative PCR validation confirming distinct temporal patterns of transcript regulation, including those involved in cardiac remodeling and survival signaling, as well as numerous
cytokines. Although Gef infusion alone did not significantly alter
cytokine expression, it abrogated the Iso-mediated changes in a majority of the βAR-sensitive
cytokines, including CCL2 and TNF-α. Additionally, the impact of βAR-dependent EGFR transactivation on the acute regulation of
cytokine transcript expression was assessed in isolated cardiomyocytes and in cardiac fibroblasts, where the majority of Iso-dependent, and EGFR-sensitive, changes in
cytokines occurred. Overall, coincident with changes in cardiac structure and contractility, βAR stimulation dynamically alters cardiac transcript expression over time, including numerous
cytokines that are regulated via EGFR-dependent signaling.