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01-07-2011 | Original Contribution

EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy

Authors: Giovanni Esposito, Cinzia Perrino, Alessandro Cannavo, Gabriele G. Schiattarella, Francesco Borgia, Anna Sannino, Gianluigi Pironti, Giuseppe Gargiulo, Luigi Di Serafino, Anna Franzone, Laura Scudiero, Paolo Grieco, Ciro Indolfi, Massimo Chiariello

Published in: Basic Research in Cardiology | Issue 4/2011

Abstract

Urotensin II (UTII) and its seven trans-membrane receptor (UTR) are up-regulated in the heart under pathological conditions. Previous in vitro studies have shown that UTII trans-activates the epidermal growth factor receptor (EGFR), however, the role of such novel signalling pathway stimulated by UTII is currently unknown. In this study, we hypothesized that EGFR trans-activation by UTII might exert a protective effect in the overloaded heart. To test this hypothesis, we induced cardiac hypertrophy by transverse aortic constriction (TAC) in wild-type mice, and tested the effects of the UTII antagonist Urantide (UR) on cardiac function, structure, and EGFR trans-activation. After 7 days of pressure overload, UR treatment induced a rapid and significant impairment of cardiac function compared to vehicle. In UR-treated TAC mice, cardiac dysfunction was associated with reduced phosphorylation levels of the EGFR and extracellular-regulated kinase (ERK), increased apoptotic cell death and fibrosis. In vitro UTR stimulation induced membrane translocation of β-arrestin 1/2, EGFR phosphorylation/internalization, and ERK activation in HEK293 cells. Furthermore, UTII administration lowered apoptotic cell death induced by serum deprivation, as shown by reduced TUNEL/Annexin V staining and caspase 3 activation. Interestingly, UTII-mediated EGFR trans-activation could be prevented by UR treatment or knockdown of β-arrestin 1/2. Our data show, for the first time in vivo, a new UTR signalling pathway which is mediated by EGFR trans-activation, dependent by β-arrestin 1/2, promoting cell survival and cardioprotection.

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Title: EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy
Authors: Giovanni Esposito
Cinzia Perrino
Alessandro Cannavo
Gabriele G. Schiattarella
Francesco Borgia
Anna Sannino
Gianluigi Pironti
Giuseppe Gargiulo
Luigi Di Serafino
Anna Franzone
Laura Scudiero
Paolo Grieco
Ciro Indolfi
Massimo Chiariello
Publication date: 01-07-2011
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 4/2011
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-011-0163-2

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EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy

Abstract

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