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Title

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

AuthorsArechederra, María; González-Nuñez, María; Gutiérrez-Uzquiza, Álvaro; Cruz-González, Ignacio; Guerrero Arroyo, María del Carmen ; López-Novoa, José M.; Porras, Almudena
KeywordsHepatocyte growth factor
Met
Cardiomyocytes
Oxidative stress
Heart
p38MAPK
Issue Date2013
PublisherElsevier
CitationBiochimica et Biophysica Acta - Molecular Basis of Disease 1832(12): 2204-2215 (2013)
AbstractHepatocyte 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.
Descriptionet al.
Publisher version (URL)http://dx.doi.org/10.1016/j.bbadis.2013.08.008
URIhttp://hdl.handle.net/10261/134355
DOI10.1016/j.bbadis.2013.08.008
Identifiersdoi: 10.1016/j.bbadis.2013.08.008
issn: 0925-4439
Appears in Collections:(IBMCC) Artículos
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