Resveratrol Inhibits Cardiac Hypertrophy And The Underlying Mechanism

Background Pathological cardiac hypertrophy is an important cause of heart failure and death.The imbalance of protein synthesis and degradation in cardiomyocytes serves as the main mechanism leading to cardiac hypertrophy.The ubiquitin-proteasome system(UPS)is the primary pathway regulating intracellular protein degradation.As a polyphenolic compound,resveratrol(RES)exhibits anti-inflammatory,anti-oxidant,and anti-tumor effects.Recent studies have found that RES shows protective effects on various cardiovascular diseases(atherosclerosis,ischemia/reperfusion,metabolic syndrome,and heart failure),but the molecular mechanism by which resveratrol regulates cardiac hypertrophy remains unclear.Object This study was to investigate the effects of RES on cardiac hypertrophy and cardiac function,and to elucidate the molecular mechanism of RES to protect cardiac hypertrophy,and to provide new strategies and methods for intervention of cardiac hypertrophy.Methods 1.Establishment of animal model: The mouse model of cardiac hypertrophy was established by pressure overload induced by transverse aortic constriction(TAC,2 weeks).2.Animal grouping and RES treatment: male C57BL/6 mice(n=40)were randomly assigned to 4 groups: sham group,TAC group,sham+RES(50 mg/kg/day)group and TAC+RES(50 mg/kg/day)group.For experiment of RES prevention,RES(50 mg/kg/day)treatment was started one week before TAC surgery;when RES was used to reversal of cardiac hypertrophy,RES(50 mg/kg/day)was treated at 2 weeks after TAC surgery.Mice were pretreated with the PTEN specific inhibitor VO-OHpic(10 mg/kg/day)to evaluate the effect of RES on PTEN protein stability.3.Experimental technique: systolic or diastolic function was assessed by M-mode echocardiography and pressure-volume curve analysis at 2 or 4 weeks of sham or TAC surgery;heart size was measured by H&E staining.Wheat germ cell agglutinin(WGA)staining was used to detect myocardial cell size;Western blot and real-time quantitative PCR(q PCR)were used to detect protein expression of signaling mediators and gene expression levels of related markers.Enzyme substrate method was used to detect 26 S proteasome activity in myocardium.Results 1.RES treatment significantly improved TAC-induced cardiac dysfunction(as indexed by decreased EF% and FS%)and cardiac hypertrophy [as reflected by increased decreased heart weight to body weight(HW/BW)and heart weight to tibia length(HW/TL)ratios,LV wall thickness,cardiomyocyte cross-sectional area,as well as gene expression levels of ANF and BNP] after 2 weeks.2.Administration of RES markedly reversed pre-established myocardial dysfunction and hypertrophy after TAC stress.3.RES treatment inhibited the expression and activities of immunoproteasome catalytic subunits induced by TAC,leading to suppressed immunoproteasome-mediated PTEN degradation,which in turn blocked ATK/m TOR signaling and AMPK inactivation.4.Treatment of PTEN inhibitor significantly blocked RES-mediated inhibition of cardiac dysfunction and hypertrophy.Conclusion: The present study has revealed that RES exhibits a significant protective effect on cardiac dysfunction and hypertrophy.Mechanistically,RES inhibits PTEN degradation and activation of AKT/m TOR signaling pathway by reducing the activity of immunoproteasome.These results provide a new approach to the prevention and treatment of pathological cardiac hypertrophy.