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MEF2C Silencing Attenuates Load-Induced Left Ventricular Hypertrophy by Modulating mTOR/S6K Pathway in Mice

2009; Public Library of Science; Volume: 4; Issue: 12 Linguagem: Inglês

10.1371/journal.pone.0008472

1932-6203

Ana Helena Macedo Pereira, Carolina F.M.Z. Clemente, Alisson C. Cardoso, Thais H. Theizen, Silvana A. Rocco, Carla C. Judice, Maria Carolina Guido, Vinicius Pascoal, Íscia Lopes‐Cendes, José R. Matos‐Souza, Kleber G. Franchini,

Cardiomyopathy and Myosin Studies

Background The activation of the members of the myocyte enhancer factor-2 family (MEF2A, B, C and D) of transcription factors promotes cardiac hypertrophy and failure. However, the role of its individual components in the pathogenesis of cardiac hypertrophy remains unclear. Methodology/Principal Findings In this study, we investigated whether MEF2C plays a role in mediating the left ventricular hypertrophy by pressure overload in mice. The knockdown of myocardial MEF2C induced by specific small interfering RNA (siRNA) has been shown to attenuate hypertrophy, interstitial fibrosis and the rise of ANP levels in aortic banded mice. We detected that the depletion of MEF2C also results in lowered levels of both PGC-1α and mitochondrial DNA in the overloaded left ventricle, associated with enhanced AMP:ATP ratio. Additionally, MEF2C depletion was accompanied by defective activation of S6K in response to pressure overload. Treatment with the amino acid leucine stimulated S6K and suppressed the attenuation of left ventricular hypertrophy and fibrosis in the aforementioned aortic banded mice. Conclusion/Significance These findings represent new evidences that MEF2C depletion attenuates the hypertrophic responses to mechanical stress and highlight the potential of MEF2C to be a target for new therapies to cardiac hypertrophy and failure.