MEF2C Silencing Attenuates Load‐Induced Hypertrophy and Energetic Metabolism in Mice Left Ventricle

Abstract

Aim: Myocyte enhancer factor 2C (MEF2C) transcription factor has been suspected to play a critical role in coordinating the proper response of cardiac myocytes to hypertrophic stimuli. However, a better understanding of the role of MEF2C in cardiac hypertrophy has been hampered by the fact the loss‐of‐function models of MEF2C in the heart do not survive to adult life. In the present study, we used an interference RNA strategy to investigate the role of MEF2C in the hypertrophic growth induced by pressure overload in mice left ventricle (LV).Methods: siRNA targeted to MEF2C was delivery (30 μg) through the jugular vein of mice in the day before the surgery to establish transverse aortic constriction (TAC).Results: siRNA administration induced prolonged MEF2C silencing (70 to 50% up to 15 days) in both control and TAC mice. MEF2C silencing was also confirmed in myocytes harvested from LV. Myocardial MEF2C silencing was accompanied by a marked attenuation of left ventricular hypertrophy and in the increases of the hypertrophic marker β‐myosin heavy chain but it did not affect the typical myocardial fibrosis of TAC mice. Furthermore, we observed no significant change in LV diameter or fractional shortening in TAC mice treated with siRNA targeted to MEF2C, despite the lack of increase in LV wall thickness in response to pressure overload. MEF2C silencing was also demonstrated to be accompanied by an increase in the AMP:ATP ratio in overloaded LV possibly reflecting the lack of proper mitochondrial biogenesis.Conclusion: These findings suggest that MEF2C modulates multiple aspects of cardiac hypertrophy induced by mechanical stress, including the expression of sarcomeric genes and the changes in the energetic metabolism.