temporal and gefitinib-sensitive regulation of cardiac cytokine expression via chronic beta-adrenergic receptor stimulation.pdf

Chronic stimulation
of -adrenergic receptors (AR) 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 AR-sensitive cytokines, including CCL2 and TNF-.
Additionally, the impact of AR-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,
AR stimulation dynamically alters cardiac transcript expression over
time, including numerous cytokines that are regulated via EGFRdependent
signaling.