Beneficial Effects Of Atorvastatin On Left Ventricular Remodeling In Spontaneously Hypertensive Rats

BackgroundMore and more evidences established that statins, HMG-CoA reductase inhibitors, not only effectively reduced serum cholesterol level, but also exerted pleiotropic beneficial effects on cardiovascular disease, including improvement of endothelial function, reduction of plaque thrombogenicity, prevention of cardiac hypertrophy or remodeling. However, these effects could not be completely explained by their cholesterol-lowering property. As a kind of genetic disease, hypertension is always accompanied by increase in left ventricular wall, ventricular expansion and interstitial fibrosis. The adaptive process, so-called left ventricular remodeling, is involved in many mechanisms. In addition to blood pressure, at cellular level, the imbalance of cell proliferation and apoptosis, intracellular Ca²⁺ concentration and the disorder of vasoactive factors have been identified as the major mechanisms for the control of ventricular remodeling. Recently, much attention about the beneficial effect of statins on myocardial hypertrophy and its possible mechanisms has been abttracted by people. Furthermore, our previous study also reported the beneficial effect of atorvastatin on amelioration of the aorta remodeling in spontaneously hypertensive rats (SHR). However, the potential mechanisms underlying these effects are still not fully elucidated.ObjectiveIn the present study, we further investigated the effect of atorvastatin on left ventricular remodeling in SHR and following explored the underlying mechanisms involved.MethodsTwelve SHR were randomized to receive either distilled water (SHR-DW group, n=6) or atorvastatin (SHR-ATV group, n=6) for 10 weeks. The age-matched Wistar-Kyoto rats (WKY) gavaged by distilled water were used as normal controls (WKY group, ?=6). By using these worked rats, we observed the effects of atorvastatin on cardiac hypertrophy and fibrosis, and investigated atorvastatin induced cell apoptosis and p27 protein expression in cardiomyocytes. In addition, we observed the effects of atorvasatin on the expression levels of HMG-CoA reductase (HMGR), farnesyl diphosphate synthase (FDS), farnesyltransferase (FT) and sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) and phospholamban (PLB), both at their mRNA and protein levels. Furthermore, serum nitric oxide (NO) content and plasm endothelin-1 (ET-1) concentration, as well as serum lipids level and blood pressure were also detected in this study.ResultsDuring the experimentalperiod, we found that:1. Comparison of the SHR-DW group and WKY group:(1) The serum lipids levels including TC\ TG> LDL-C and HDL-C were significantly decreased in SHR-DW group.(2) SBP in SHR-DW group was physiologically elevated, while WKY group had no significant changes in this period.(3) The hypertrophic indexes such as heart weight to body weight ratio (HW/BW), left ventricular weight to body weight ratio (LVW/BW) and cardiomyocyte transverse diameter (TDM) in SHR-DW group were increased remarkably, as well as myocardial hydroxyproline (Hyp) and collagen content.(4) Compared to WKY group, the positive rate of cardiomyocytes apoptosis and p27 protein expression in SHR-DW group were much lower.(5) The expression of myocardial HMGR, FDS and FT in SHR-DW group , both at their mRNA and protein levels, were significant increased in SHR-DW group;and its SERCA expression and activity were significant decreased when compared to WKY group. However, the expression levels of PLB had no significant changes between the two groups. Consequently, the ratio of PLB to SERCA (PLB/SERCA) protein level in SHR-DW group was much higher than WKY group.(6) In SHR-DW group, serum NO content decreased and plasm ET-1 concentration increased, all of which reached statistical significance compared to WKY group.2. Comparison of the SHR-ATV group and the above two groups:(1) Compared to SHR-DW group and WKY group, the levels of TC> TG^ LDL-C in SHR-ATV group were significantly decreased.(2) A significant reduction in SBP was found in SHR-ATV group when compared to SHR-DW group. However, compared to WKY group, the blood pressure level in SHR-ATV group was still higher.(3) The hypertrophic indexes, as well as myocardial Hyp and collagen content in SHR-ATV group were decreased remarkably compared to SHR-DW group, almost reaching those of WKY.(4) Compared to SHR-DW group, the positive rate of cardiomyocytes apoptosis and p27 protein expression in SHR-ATV group were restored and slightly higher than WKY group but not reach the statistical significance.(5) A lower expression of myocardial HMGR, FDS and FT, and a higher expression of myocardial SERCA in SHR-ATV group, both at their mRNA and protein levels, along with a higher SERCA activity were found in SHR-ATV group. The expression levels of PLB in SHR-ATV group, however, had no significant changes compared to the two groups. Additionly, the PLB/SERCA protein ratio in SHR-ATV group was thus decreased compared to SHR-DW group.(6) Compared to SHR-DW group, SHR-ATV group showed an increased serumSHR-ATV group were still not restored to the levels of WKY group.Conclusions1. Administration of atorvastatin to SHR not only effectively reduced the serum lipids levels, but also reversed the progress of left ventricular remodeling in SHR.2. The compound's ability to facilitate cardiomyocytes apoptosis and p27 expression, decrease HMGR, FDS and FT expression, upregulate SERCA expression and activity, decrease PLB/SERCA protein ratio and decrease ET-1 level and increase NO activity may serve as the underlying mechanisms of this action. In addition, the blood-pressure lowering effect of atorvastain may benefit to prevent the development of left ventricular remodeling.