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Met signaling in cardiomyocytes is required for normal cardiac function in adult mice Arechedera, María Carmona-Mejías, Rita María González-Núñez, María Gutiérrez-Urquiza, Álvaro Bragado, Paloma Cruz-González, Ignacio Cano, Elena Guerrero, Carmen Sánchez, Aránzazu López-Novao, José Miguel Schneider, Michael D. Maina, Flavio Muñoz-Chápuli-Oriol, Ramón Porras, Almudena Cardiología 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. 2025-01-14T11:15:20Z 2025-01-14T11:15:20Z 2025-01-14T11:15:20Z 2013-12 journal article María Arechederra, Rita Carmona, María González-Nuñez, Álvaro Gutiérrez-Uzquiza, Paloma Bragado, Ignacio Cruz-González, Elena Cano, Carmen Guerrero, Aránzazu Sánchez, José Miguel López-Novoa, Michael D. Schneider, Flavio Maina, Ramón Muñoz-Chápuli, Almudena Porras, Met signaling in cardiomyocytes is required for normal cardiac function in adult mice, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1832, Issue 12, 2013, Pages 2204-2215, ISSN 0925-4439, https://doi.org/10.1016/j.bbadis.2013.08.008 https://hdl.handle.net/10630/36300 10.1016/j.bbadis.2013.08.008 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier