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Updated: May 8, 2026
Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 24, 2013
Met signaling in cardiomyocytes is required for normal cardiac function in adult mice
María Arechederra1, Rita Carmona, María González-Nuñez
1Departamento 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.
Insights
Hepatocyte growth factor (HGF) signaling is crucial for adult heart function. Disrupting HGF/Met in cardiomyocytes leads to cardiac damage and dysfunction by impairing antioxidant defenses and increasing oxidative stress.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Signaling
Background:
- Hepatocyte growth factor (HGF) and its receptor, Met, are vital for development.
- The role of HGF/Met signaling in adult heart physiology remains unclear.
- Investigating HGF/Met's necessity in cardiomyocytes for heart development and adult function.
Purpose of the Study:
- To determine the role of cardiomyocyte HGF/Met signaling in cardiac development and adult function.
- To elucidate the molecular mechanisms underlying cardiac dysfunction upon Met receptor inactivation in cardiomyocytes.
Main Methods:
- Conditional inactivation of the Met receptor in cardiomyocytes using the Cre-α-MHC mouse line (α-MHCMet-KO).
- Assessment of cardiac development, function, and histology in α-MHCMet-KO mice.
- Analysis of antioxidant enzyme expression, activity, reactive oxygen species (ROS) levels, and signaling pathways (TGF-β, p38MAPK).
Main Results:
- α-MHCMet-KO mice exhibited normal embryonic and postnatal heart development.
- Adult male α-MHCMet-KO mice developed cardiomyocyte hypertrophy, fibrosis, and systolic dysfunction by 9 months.
- Impaired antioxidant defenses (catalase, superoxide dismutase), increased ROS, elevated TGF-β, and reduced p38MAPK activation were observed.
- HGF/Met signaling regulates antioxidant enzymes in cardiomyocytes via p38α activation.
Conclusions:
- Cardiomyocyte HGF/Met signaling is essential for maintaining physiological cardiac function in adult mice.
- This signaling pathway acts as an endogenous regulator of heart function by controlling oxidative stress.
- Dysregulation of HGF/Met signaling contributes to cardiac pathology through oxidative imbalance.
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.
