title: Met signaling in cardiomyocytes is required for normal cardiac function in adult mice.
abstract: 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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, 28040 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Arechederra
authors.forename: Rita
authors.initials: R
authors.lastname: Carmona
authors.forename: María
authors.initials: M
authors.lastname: González-Nuñez
authors.forename: Alvaro
authors.initials: A
authors.lastname: Gutiérrez-Uzquiza
authors.forename: Paloma
authors.initials: P
authors.lastname: Bragado
authors.forename: Ignacio
authors.initials: I
authors.lastname: Cruz-González
authors.forename: Elena
authors.initials: E
authors.lastname: Cano
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerrero
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Sánchez
authors.forename: José Miguel
authors.initials: JM
authors.lastname: López-Novoa
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
authors.forename: Ramón
authors.initials: R
authors.lastname: Muñoz-Chápuli
authors.forename: Almudena
authors.initials: A
authors.lastname: Porras
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004562:Electrocardiography; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D019426:Integrases; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D002374:Catalase; D013482:Superoxide Dismutase; D003576:Electron Transport Complex IV; D019859:Proto-Oncogene Proteins c-met; D048051:p38 Mitogen-Activated Protein Kinases; C045073:Cre recombinase; D019426:Integrases
keywords: Cardiomyocytes; Heart; Hepatocyte growth factor; Met; Oxidative stress; p38MAPK