Research In Effect Of Atorvastatin On Left Ventricular Function And Its Mechanism In Spontaneously Hypertensive Rats

Background:Previous studies have demonstrated that statins,the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase,have many effects beyond lipid-lowering,which make them of potential benefit in patients with various heart diseases.Recently,statins were shown to improve cardiac function in clinical and experimental studies,andthis protective effect is being confirmed by growing evidence.Also,intracellular Ca²⁺homeostasis is one of the critical factors responsible for efficient myocardial function,and abnormalities of Ca²⁺-regulating proteins in myocardium are closely involved in thepathogenesis of cardiac dysfunction.However,it is still unclear whether the beneficialeffect of statins on cardiac function is associated with alterations of Ca²⁺-regulatingproteins.Objective:In this study,we investigated the effect of atorvastatin on cardiac function inspontaneously hypertensive rats(SHRs),focusing in particular on its impact on theexpression of myocardium Ca²⁺-regulating proteins:sarcoplasmic reticulum Ca²⁺-adenosine triphosphatase(SERCA),phospholamban(PLB)and its phosphorylated form(phosphorylated PLB).We tried to provide novel in vivo evidence for the potentialmechanism that statin might improve cardiac dysfunction in SHRs via affecting thebehaviors of myocardium Ca²⁺-regulating proteins.Methods:8-week-old male SHRs and Wistar Kyoto rats(WKYs)were given(by gavage for10 weeks)either 1 ml distilled water,atorvastatin(50 mg/kg/day),amlodipine(2mg/kg/day),or both,mixed with 1 ml distilled water.Amlodipine here was used as adrug control for blood pressure.Systolic blood pressure(SBP)was measured weekly bythe tail-cuff method.Echocardiographic measurement was performed biweekly duringthe experiment.Mean arterial pressure(MAP)and the positive and negative firstderivatives of LV pressure(±dp/dt max)were measured by hemodynamic studies.Blood lipid levels were then detected.Pathologic studies was used for evaluatingtransdiameter of cardiomyocyte(TDM)and collagen volume fraction(CVF).Theexpression of SERCA,PLB and phosphorylated PLB protein level were detected byWestern blot analysis.IL-6,IL-10 and TNF-αlevels were quantified,as well as SERCAactivity and hydroxyproline content.Result:SBP of SHRs increase gradually at the age of 8～18 week,accompanied withhigher LVW/BW ratio,larger size of TDM,increased myocardium fibrotic infiltrationand hydroxyproline content,which mean cardiac hypertrophy.Also,SHRs haveabnormal inflammatory cytokine concentrations,with higher IL-6 and TNF-αlevels andlower IL-10 level.Both atorvastatin and amlodipine reduce systolic blood pressure,improve LV remodeling and myocardium inflammatory cytokine markers in SHRs.Inaddition,compared to WKYs,SHRs show decreases in gene expression of SERCA andphosphorylated PLB,and reduction in SERCA activity in left ventricular myocardium, as well as gradually reduced cardiac systolic and diastolic function.Furthermore,weshowed that atorvastatin preserved cardiac dysfunction in SHRs,accompanied bypositive alterations in calcium regulatory proteins,with up-regulation in expression ofSERCA and phosphorylated PLB,and with improvement of SERCA activity.Conclusions:It can not conclude from our data that the improvement of left ventricular functionin SHRs is due either to the beneficial effects of atorvastatin and amlodipine oninflammatory markers,or reduction in blood pressure,or their effects on remodeling.Alterations in Ca2+-regulating proteins may contribute to the cardiac dysfunction inSHRs,and the HMG-CoA reductase inhibitor atorvastatin modulate the proteinexpression and increase the activity of SERCA,which effectively preserve leftventricular function and may be one of the mechanisms of statins' beneficial effects oncardiac dysfunction in hypertensive rats.