Effects of varying doses of simvastatin on protein kinase A in immature rabbits with chronic heart failure

Abstract

Objective To investigate the effects of varying doses of simvastatin (SIM) on protein kinase A(PKA), ventricular remodeling and heart function in immature rabbits with chronic heart failure (CHF), to explore the possible mechanisms for simvastatin on CHF. Methods Sixty male immature rabbits were randomly divided into 5 groups: control (CON) group, CHF model group, small-dose simvastatin (SD-SIM) group[SIM concentration was 0.3 mg/(kg·d)], medium-dose simvastatin (MD-SIM)group[SIM concentration was 1.5 mg/(kg·d)], and the high-dose simvastatin (HD-SIM)group[SIM concentration was 3.0 mg/(kg·d)]. The general condition of immature rabbits in the experiment group was evaluated.Color doppler ultrasonography was used to detect the left ventricular structure and the function.The left ventricular myocardium was taken and fixed in paraformaldehyde (40 g/L). The expression of PKA was evaluated by immunohistochemical assay. Results In CON group, the rabbits were all alive; in the other groups, most immature rabbits were unhairing, with diet reduction, weight lose and sluggish with hyperkeratosis.Overall survival rate was 82%(49/60 cases). The mortality rate in CHF model group was significantly higher than that in the MD-SIM group(41.7% vs 8.3%, P<0.05). Compared with the CON group, left ventricular ejection fraction(LVEF) in the SD-SIM group, HD-SIM group and CHF model group all dropped sharply (all P<0.01), while the left ventricular end diastolic diameter (LVEDd) and left ventricular end systolic diameter (LVESd) increased markedly (all P<0.01). Compared with CHF model group, LVEDd and LVESd decreased and LVEF increased significantly in SD-SIM group, HD-SIM group and MD-SIM group(all P<0.05), the effects of MD-SIM group was the best(P<0.05). LVEF in MD-SIM group increased significantly compared with SD-SIM group, HD-SIM group and CHF model group (all P<0.05). PKA expression in SD-SIM group, MD-SIM group and HD-SIM group increased significantly compared to the CHF model group and CON group (all P<0.01). Compared with the SD-SIM group and HD-SIM group, the expression of MD-SIM group significantly increased (P<0.05). Conclusions Simvastatin can reverse the left ventricular remodeling and improve the heart function of immature rabbits with CHF.The effect of MD-SIM was the best.The mechanism of simvastatin may be correlated to up-regulating the expression of PKA. Key words: Simvastatin; Adriamycin; Chronic heart failure; Protein kinase A