Protective Effect And Molecular Mechanism Of Acacetin On Myocardial Hypertrophy

Introduction:Myocardial hypertrophy is a compensatory-adaptive response of heart to various injury stimuli,which can maintain cardiac output and ejection fraction at early stage.However,long-term cardiac hypertrophy eventually decompensates,leading to heart failure.Angiotensin Ⅱ(Ang Ⅱ)plays a very important role in the pathogenesis and development of myocardial hypertrophy Previous studies have reported that the natural flavonoid,acacetin has a protective effect aginst myocardial ischermia-reperfusion injury.The present study investiagtes the effects of acacetin on myocardial hypertrophy and potential molecular mechanisms in ex vivo and in vivo modelsMethods:In cultured primary neonatal rat cardiomyocytes(NRCMs)and H9C2 rat cardiomyoblasts.Cellular hypertrophy was induced by Ang Ⅱ(100 nM)and the cellular hypertrophy was assessed by measuring the surface area.Flow cytometry was used to determine the cellular ROS.Western blots were employed to determin protein levels related to cardiac hypertrophy,redox enzymes,apoptosis-related proteins,inflammatory factors and energy metabolism related proteins were detected Myocardial hypertrophy model was established in rats by abdominal aortic coarctation(TAC).Heart function was determined with echocardiography and direct intraventricular pressure measurement.Gene silencing approach was used to detect the potential molecular target of acacetin for protection against myocardial hypertrophyResults:It was found that acacetin significantly inhibited cardiomyocyte hypertrophy induced by Ang Ⅱ in both NRCMs and H9C2 rat cardiomyoblasts in a concentration-dependent manneIr,decreased the protein levels of BNP,β-MHC,Bax,IL-6 and the release of ROS in cells induced by Ang Ⅱand increased expression of Nrf2,SODs,HO-1,Bcl-2,p-AMPK,PGC-1α and PPARα.The AMPK inhibitor Compound C reduced the protective effect of acacetin against myocardial hypertrophy induced by Ang Ⅱ.In TAC animals,acacetin significantly improved the reduction of cardiac function and energy metabolic proteins,and the increase of ventricular wall thickness and myocardial protein BNP.In H9C2 cardiormyoblasts,silence of Sirtl revealed the protective effect of acacetin against myocardial hypertrophy is related to activation of Sirtl/AMPK/PGC-la signal pathway.Conclusions:The results suggest that acacetin confers protection against myocardial hypertrophy by activating Sirtl/AMPK/PGC-1α signal pathway,thereby reducing oxidative stress,apoptosis and inflammatory response,which can prevent the disorder of glycolipid energy metabolism in cardiomyocytes.This study suggests that acacetin may be a drug candidate for treating/preventing myocardial hypertrophy.