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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

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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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Acknowlegements

This work has been supported by the grant PRIN 2007 (No. 2007WS3JL3) from the Ministero dell’Università e della Ricerca Scientifica to M.C.; Cinzia Perrino MD PhD has been supported, in part, by a Grant “L’Oreal—Italia—For women in Science 2008”. The authors kindly thank Dr. Howard A. Rockman (Duke University, Durham NC) for supplying the EGFR-FLAG, EGFR-GFP, β-arrestin-GFP plasmids. This paper is dedicated to the memory of Professor Massimo Chiariello MD, passed away on March 23rd 2010.

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Authors and Affiliations

  1. Division of Cardiology, Federico II University of Naples, Via Pansini 5, 80131, Naples, Italy

    Giovanni Esposito, Alessandro Cannavo, Gabriele G. Schiattarella, Francesco Borgia, Anna Sannino, Gianluigi Pironti, Giuseppe Gargiulo, Luigi Di Serafino, Anna Franzone, Laura Scudiero & Massimo Chiariello

  2. IRCCS Neuromed, Pozzilli, Italy

    Cinzia Perrino

  3. Department of Pharmaceutical and Toxicological Chemistry, Federico II University of Naples, Naples, Italy

    Paolo Grieco

  4. Division of Cardiology, University Magna Graecia, Catanzaro, Italy

    Ciro Indolfi

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  1. Giovanni Esposito
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Correspondence to Giovanni Esposito.

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G. Esposito and C. Perrino equally contributed to this work.

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Esposito, G., Perrino, C., Cannavo, A. et al. EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy. Basic Res Cardiol 106, 577–589 (2011). https://doi.org/10.1007/s00395-011-0163-2

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