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oai:docta.ucm.es:20.500.14352/1002002025-03-18T11:56:24Zcom_20.500.14352_14col_20.500.14352_15

00925njm 22002777a 4500 dc Arechederra Calderón, María author Carmona Mejías, Rita author González-Nuñez, María author Gutiérrez Uzquiza, Álvaro author Bragado Domingo, Paloma author Cruz-González, Ignacio author Cano Rincón, Elena author Guerrero Arroyo, María Del Carmen author Sánchez Muñoz, Aranzazu author López-Novoa, José Miguel author Schneider, Michael D. author Maina, Flavio author Muñoz-Chápuli, Ramón author Porras Gallo, María Almudena author 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-α-MHC mouse line (referred to as α-MHCMet-KO). Although α-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 β-MHC and ANF, was also observed. By the age of 9 months, α-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in α-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-β production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in α-MHCMet-KO mice. Consistently, we show that HGF acts through p38α 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. Arechederra M, Carmona R, González-Nuñez M, Gutiérrez-Uzquiza Á, Bragado P, Cruz-González I, et al. Met signaling in cardiomyocytes is required for normal cardiac function in adult mice. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2013;1832:2204–15. https://doi.org/10.1016/j.bbadis.2013.08.008. 0925-4439 10.1016/j.bbadis.2013.08.008 https://hdl.handle.net/20.500.14352/100200 https://doi.org/10.1016/j.bbadis.2013.08.008 Met signaling in cardiomyocytes is required for normal cardiac function in adult mice