Urotensin II (UII) and its receptor (UTR) are up-regulated in the heart under pathological conditions. Stimulation of UTR activates many signaling pathways, including mitogen-activated protein kinases (MAPK). Recent evidence also suggests that UTII might trans-activate the epidermal growth factor receptor (EGFR) in vitro. However, the in vivo effects of UII signaling inhibition have been poorly studied. In this study we hypothesized that UTII-mediated transactivation of the EGFR confers cardioprotection. To study the in vivo role of UII signaling in cardiac remodeling we induced in wild type mice myocardial infarction by coronary artery ligation (MI, n=10) and cardiac hypertrophy by transverse aortic constriction (TAC, n=10). After 7 days, MI and TAC mice were sacrificed. Following MI and TAC, 2 additional groups of mice underwent the chronic infusion of UII inhibitor (Urantide, UR, 2 umol/kg/die) by micro-osmotic pumps (MI+UR, n=8; TAC+UR, n=7). Twelve C57BL/6 mice underwent the sham procedure (SHAM, n=12). Cardiac function was evaluated by echocardiography before and 7 days after MI or TAC. As expected, TAC mice exhibited a significantly increased LV weight to body weight ratio (LVW/BW) and UR treatment did not affect cardiac hypertrophy development (TAC+UR=5.83±0.5; TAC= 6.04±0.5). Interestingly, TAC+UR mice displayed a significant impairment of cardiac function (% Fractional Shortening; TAC+UR= 45+1.5; TAC= 51+1.5; p<0.05). Following MI, UII signaling inhibition by UR did not affect the percent infarct size (MI+UR=27±3;MI 28±4, p=NS) but significantly reduced LV function expressed by % FS (MI+UR=36±1.5; MI=41±1.5; p<0.05). These abnormalities were associated with a significant increase in % LV fibrosis (MI+UR=15±1.4; MI+10±1.5; p<0.05). Interestingly, phosphorylation levels of EGFR were significantly increased in MI mice compared to sham and were significantly reduced by UR treatment. Consistently, ERK phosphorylation was significantly increased in MI compared to sham, and significantly decreased in MI and TAC mice after UR treatment. Our data show in 2 different models of cardiac remodeling that UII inhibition exerts detrimental effects on cardiac function suggesting a potential cardioprotective role of UII in heart failure
Cardioprotective Role of Urotensin (UTII)-mediated Transactivation of the EGFR / Giovanni, Esposito; Cinzia, Perrino; Capretti, Giuliana; Gabriele, Schiattarella; Anna, Franzone; Anna, Sannino; Francesco, Borgia; Giuseppe, Gargiulo; Elisa Di, Pietro; Massimo, Chiariello. - In: CIRCULATION. - ISSN 0009-7322. - 118:(2008). (Intervento presentato al convegno American Heart Association (AHA) 2008 Scientific Sessions tenutosi a New Orleans, Louisiana nel 8-12 novembre 2008).
Cardioprotective Role of Urotensin (UTII)-mediated Transactivation of the EGFR
CAPRETTI, GIULIANA;
2008
Abstract
Urotensin II (UII) and its receptor (UTR) are up-regulated in the heart under pathological conditions. Stimulation of UTR activates many signaling pathways, including mitogen-activated protein kinases (MAPK). Recent evidence also suggests that UTII might trans-activate the epidermal growth factor receptor (EGFR) in vitro. However, the in vivo effects of UII signaling inhibition have been poorly studied. In this study we hypothesized that UTII-mediated transactivation of the EGFR confers cardioprotection. To study the in vivo role of UII signaling in cardiac remodeling we induced in wild type mice myocardial infarction by coronary artery ligation (MI, n=10) and cardiac hypertrophy by transverse aortic constriction (TAC, n=10). After 7 days, MI and TAC mice were sacrificed. Following MI and TAC, 2 additional groups of mice underwent the chronic infusion of UII inhibitor (Urantide, UR, 2 umol/kg/die) by micro-osmotic pumps (MI+UR, n=8; TAC+UR, n=7). Twelve C57BL/6 mice underwent the sham procedure (SHAM, n=12). Cardiac function was evaluated by echocardiography before and 7 days after MI or TAC. As expected, TAC mice exhibited a significantly increased LV weight to body weight ratio (LVW/BW) and UR treatment did not affect cardiac hypertrophy development (TAC+UR=5.83±0.5; TAC= 6.04±0.5). Interestingly, TAC+UR mice displayed a significant impairment of cardiac function (% Fractional Shortening; TAC+UR= 45+1.5; TAC= 51+1.5; p<0.05). Following MI, UII signaling inhibition by UR did not affect the percent infarct size (MI+UR=27±3;MI 28±4, p=NS) but significantly reduced LV function expressed by % FS (MI+UR=36±1.5; MI=41±1.5; p<0.05). These abnormalities were associated with a significant increase in % LV fibrosis (MI+UR=15±1.4; MI+10±1.5; p<0.05). Interestingly, phosphorylation levels of EGFR were significantly increased in MI mice compared to sham and were significantly reduced by UR treatment. Consistently, ERK phosphorylation was significantly increased in MI compared to sham, and significantly decreased in MI and TAC mice after UR treatment. Our data show in 2 different models of cardiac remodeling that UII inhibition exerts detrimental effects on cardiac function suggesting a potential cardioprotective role of UII in heart failureI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
