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Met signaling in cardiomyocytes is required for normal cardiac function in adult mice

Autores: Arechederra Calderon, Maria; Carmona, R. ; González-Nuñez, M.; Gutiérrez-Uzquiza, A.; Bragado, P.; Cruz-González, I.; Cano, E. ; Guerrero, C.; Sánchez, A.; López-Novoa, J. M. ; Schneider, M. D. ; Maina, F. ; Muñoz-Chápuli, R. ; Porras, A. (Autor de correspondencia)
ISSN: 0925-4439
Volumen: 1832
Número: 12
Páginas: 2204 - 2215
Fecha de publicación: 2013
Hepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-¿-MHC mouse line (referred to as ¿-MHCMet-KO). Although ¿-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6 months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as ß-MHC and ANF, was also observed. By the age of 9 months, ¿-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in ¿-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-ß production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in ¿-MHCMet-KO mice. Consistently, we show that HGF acts through p38¿ to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control.