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

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.

Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

“…28,29 Our data support this hypothesis. The partial loss of cardiomyocyte Morphology of aortas and intramyocardial arteries ex vivo and estimation of wall stress, respectively.…”

Cardiac-Specific PID1 Overexpression Enhances Pressure Overload-Induced Cardiac Hypertrophy in Mice

“…However, the mechanism by which PID1 mediates its effects during the transition from cardiac hypertrophy to failure remains elusive. It is generally accepted that a mechanical signal induced by pressure overload will initiate a cascade of biological signaling transduction pathways that increase collagen synthesis and cardiomyocyte growth [13,14,15,16,17]. Previous studies have demonstrated that the AKT pathway is crucial in the process of cardiac hypertrophy [18,19,20,21].…”

Arrestins in Apoptosis

“…Similarly, arrestin-2-dependent ERK activation mediated protective effect of glutamate acting via metabotropic glutamate receptor 1 (mGluR1) against serum-deprivation-induced apoptosis (Emery et al 2010). Both arrestin-2 and arrestin-3 mediate transactivation of the epidermal growth factor (EGF) receptor by the Gq-coupled receptor of neuropeptide urotensin II (Esposito et al 2011). Urotensin II, which is expressed in the nervous, cardiovascular, and urogenital systems, and its receptor are upregulated in the pathological heart (Zhu et al 2006), and this increase seems to be protective, since treatment with urotensin II antagonist exacerbates heart pathology and promotes apoptosis of cardiomyocytes, the effect linked to reduced EGF receptor transactivation and resulting ERK activity (Esposito et al 2011).…”

“…Both arrestin-2 and arrestin-3 mediate transactivation of the epidermal growth factor (EGF) receptor by the Gq-coupled receptor of neuropeptide urotensin II (Esposito et al 2011). Urotensin II, which is expressed in the nervous, cardiovascular, and urogenital systems, and its receptor are upregulated in the pathological heart (Zhu et al 2006), and this increase seems to be protective, since treatment with urotensin II antagonist exacerbates heart pathology and promotes apoptosis of cardiomyocytes, the effect linked to reduced EGF receptor transactivation and resulting ERK activity (Esposito et al 2011). Arrestin-3 mediated the protection conferred by the angiotensin II receptor 1A to primary rat vascular smooth muscle or to HEK293 cells against hydrogen peroxide (H 2 O 2 )- or etoposide-induced apoptosis (Ahn et al 2009).…”