Abstract
BackgroundThe 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 FindingsIn 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/SignificanceThese 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.
Highlights
Hypertrophy is a common feature of many forms of heart disease
Western blot analysis indicated that MEF2C was reduced in the order of 75%, while no change could be observed in the expression of MEF2A in cells treated with siRNA targeted to MEF2C (siMEF2C), in comparison with cells treated with siGFP (Figure 1E, F)
Our results demonstrate that the depletion of MEF2C by small interfering RNA (siRNA) attenuates the hypertrophic growth of mice left ventricle in response to pressure overload, reduces hypertrophy in cardiomyocytes and diminishes interstitial fibrosis and attenuates the upregulation of ANP
Summary
Hypertrophy is a common feature of many forms of heart disease. While initially an adaptive response to increased workload and injury, in the long term cardiac hypertrophy predisposes to heart failure[1,2,3]. Among the intracellular pathways that integrate mechanical and hormonal signals, MEF2 (myocyte enhancer factors-2, members A to D) transcription factors play prominent roles in the regulation of cardiac hypertrophy and remodeling[8,9,10] In this context, many studies have shown that overall MEF2 DNA-binding activity is enhanced in cardiomyocytes in response to biomechanical and neurohormonal stimuli[11,12,13]. Recent studies performed in mice with dominant-negative MEF2D suggested that this factor is an important mediator of the pathologic left ventricular hypertrophy, as these mice displayed no cardiac hypertrophy, fibrosis or fetal gene activation in response to pressure overload[10] These evidences support the idea that MEF2 factors mediate the effects of detrimental signaling pathways in response to hypertrophic stimuli. Left ventricular hypertrophy induced by aortic banding in mice was used as a model system in this study
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