10.25376/hra.7819952.v1
Laurel A. Grisanti
Laurel
A. Grisanti
Ashley A. Repas
Ashley
A. Repas
Jennifer A. Talarico
Jennifer
A. Talarico
Jessica I. Gold
Jessica
I. Gold
Rhonda L. Carter
Rhonda L.
Carter
Walter J. Koch
Walter J.
Koch
Douglas G. Tilley
Douglas
G. Tilley
temporal and gefitinib-sensitive regulation of cardiac cytokine expression via chronic beta-adrenergic receptor stimulation.pdf
Health Research Alliance
2019
beta-adrenergic receptor
heart
remodeling
cytokine
EGFR
Cardiology (incl. Cardiovascular Diseases)
2019-03-08 13:44:39
Journal contribution
https://hra.figshare.com/articles/journal_contribution/temporal_and_gefitinib-sensitive_regulation_of_cardiac_cytokine_expression_via_chronic_beta-adrenergic_receptor_stimulation_pdf/7819952
Chronic stimulation<br>of -adrenergic receptors (AR) can promote survival signaling<br>via transactivation of epidermal growth factor receptor (EGFR)<br>but ultimately alters cardiac structure and contractility over time, in<br>part via enhanced cytokine signaling. We hypothesized that chronic<br>catecholamine signaling will have a temporal impact on cardiac<br>transcript expression in vivo, in particular cytokines, and that EGFR<br>transactivation plays a role in this process. C57BL/6 mice underwent<br>infusion with vehicle or isoproterenol (Iso) gefitinib (Gef) for 1 or<br>2 wk. Cardiac contractility decreased following 2 wk of Iso treatment,<br>while cardiac hypertrophy, fibrosis, and apoptosis were enhanced at<br>both timepoints. Inclusion of Gef preserved contractility, blocked<br>Iso-induced apoptosis, and prevented hypertrophy at the 2-wk timepoint,<br>but caused fibrosis on its own. RNAseq analysis revealed<br>hundreds of cardiac transcripts altered by Iso at each timepoint with<br>subsequent RT-quantitative PCR validation confirming distinct temporal<br>patterns of transcript regulation, including those involved in<br>cardiac remodeling and survival signaling, as well as numerous<br>cytokines. Although Gef infusion alone did not significantly alter<br>cytokine expression, it abrogated the Iso-mediated changes in a<br>majority of the AR-sensitive cytokines, including CCL2 and TNF-.<br>Additionally, the impact of AR-dependent EGFR transactivation on<br>the acute regulation of cytokine transcript expression was assessed in<br>isolated cardiomyocytes and in cardiac fibroblasts, where the majority<br>of Iso-dependent, and EGFR-sensitive, changes in cytokines occurred.<br>Overall, coincident with changes in cardiac structure and contractility,<br>AR stimulation dynamically alters cardiac transcript expression over<br>time, including numerous cytokines that are regulated via EGFRdependent<br>signaling.