| First Author | Arechederra M | Year | 2013 |
| Journal | Biochim Biophys Acta | Volume | 1832 |
| Issue | 12 | Pages | 2204-15 |
| PubMed ID | 23994610 | Mgi Jnum | J:204089 |
| Mgi Id | MGI:5529574 | Doi | 10.1016/j.bbadis.2013.08.008 |
| Citation | Arechederra M, et al. (2013) Met signaling in cardiomyocytes is required for normal cardiac function in adult mice. Biochim Biophys Acta 1832(12):2204-15 |
| abstractText | 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-alpha-MHC mouse line (referred to as alpha-MHCMet-KO). Although alpha-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 beta-MHC and ANF, was also observed. By the age of 9 months, alpha-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in alpha-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-beta production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in alpha-MHCMet-KO mice. Consistently, we show that HGF acts through p38alpha 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. |
