The Effects And Mechanisms Of Simvastatin On Ventricular Remodeling And Heart Function In Chronic Heart Failure Rabbit Models

Objection: This study was to evaluate the effects of simvastatin on ventricular remodeling and heart function and investigate the mechanisms of cardioprotective effects of simvastatin.Methords: 24 rabbits were divided 4 groups, group I: received sham operation as health control. In other groups, aortic regurgitation and coarctation of ascending aorta were operated in rabbits. Group II was received no drugs. In group III, rabbits were given simvastatin 5mg·kg-1·d-1 after the operation. In group IV, rabbits were given simvastatin 5mg·kg-1·d-1 after 4 weeks of operation. At begin and end of treatment period, Echocardiographic evaluations were performed and left ventricular end diastolic pressure was measured with catheter. At the end of experiment, heart weight, left ventricular weight, body weight, heart weight/body weight radio, left ventricular weight/body weight radio were measured.Myocardial apoptosis identified by in situ dUTP nick-end labeling method and apoptotic index (AI) was calculated.Western blotting analysed RhoA expression in cardiomyocyte membrane and cyclin B1 expression in cardiomyocytes cytosol. Rho GTPases activity was determined by [γ-32P] GTP- binding assays. RT-PCR was used to evaluate peroxisome proliferator-activated receptor (PPAR)γmRNA expression. Western blotting analysed PPARγexpression in cardiomyocytes nuclear.Electropharesis mobility shift assay (EMSA) System was used to evaluate NF-κB activity.Western blotting analysed NF-κB expression in cardiomyocytes nuclear. Glycogen Synthase Kinase (GSK)3βactivity was determined by immunoprecipitation.Western blotting analysed GSK3βexpression in cardiomyocytes cytosol andβ-catenin expression in cardiomyocytes unclear. Results: Compared with CHF rabbits, in rabbits received early and late treatment of simvastatin, the heart weight, left ventricular weight, heart weight/body weight radio were significantly less (p<0.05-0.01, respectively), The IVSd, LVIDs were significantly decreased (p<0.05-0.01, respectively), the EF and FS were significantly higher (p<0.05- 0.01, respectively), The apoptotic index (AP) was significantly less (p<0.01), The LVEDP were significantly lower (p<0.05), cardiomyocyte size decreased. In early treatment group, left ventricular weight/body weight radio, LVIDd and LVPWd were significantly less than CHF rabbits also (p<0.05-0.01, respectively).In rabbits treated by simvastatin, the expression of RhoA in cardiomyocytes membrane and cyclin B1 in cardiomyocytes cytosol were significantly decreased (p<0.01, respectively). Simvastatin significantly diminished the activity of Rho GTPase (p<0.01, respectively).Simvastatin significantly promoted the PPARγmRNA and protein expression (p<0.01, respectively). The expression and activity of NF-κB were sinificantly inhibited in rabbits treated by simvastatin (p<0.01, respectively).Simvastatin significantly promoted the activity of GSK3βin cardiomyocytes cytosol and significantly reduced the expression ofβ-catenin in cardiomyocytes unclear (p<0.01, respectively).Conclusion: Given simvastatin in chronic heart failure rabbit models could prevent heart enlarge and inhibit the development of cardiac hypertrophy and prevent the cardiomyocytes apoptosis, improve cardiac function. The mechanisms include: (1) Simvastatin inhibite the expression of RhoA in cardiomyocytes membrane and Rho GTPase activity in cardiomyocytes cytosol.Simvastatin decreae expression of cyclinB1 in cardiomyocytes cytosol. (2) Simvastatin promote PPARγmRNA and protein expression in cardiomyocytes nuclear, inhibite NF-κB expression and activity in cardiomyocytes nuclear. (3)Simvastatin promote GSK3βactivity in cardimyocytes cytosol and reduce the expression ofβ-catenin in cardiomyocytes nuclear.