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

Esposito, G.; Perrino, C.; Cannavo, A.; Schiattarella, G.G.; Borgia, F.; Sannino, A.; Pironti, G.; Gargiulo, G.; Di Serafino, L.; Franzone, A.; Scudiero, L.; Grieco, P.; Indolfi, C.; Chiariello, M.

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

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Item Type:	Article
Title:	EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy
Creators Name:	Esposito, G., Perrino, C., Cannavo, A., Schiattarella, G.G., Borgia, F., Sannino, A., Pironti, G., Gargiulo, G., Di Serafino, L., Franzone, A., Scudiero, L., Grieco, P., Indolfi, C. and Chiariello, M.
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.
Keywords:	Urotensin II, EGFR, Cardiac Hypertrophy, β-Arrestin, Animals, Mice
Source:	Basic Research in Cardiology
ISSN:	0300-8428
Publisher:	Steinkopff
Volume:	106
Number:	4
Page Range:	577-589
Date:	July 2011
Official Publication:	https://doi.org/10.1007/s00395-011-0163-2
PubMed:	View item in PubMed

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