阿托伐他汀通过Nrf2/HO-1改善慢性心力衰竭大鼠心功能的作用及机制研究

Effect of atorvastatin on improving cardiac function of rats with chronic heart failure through Nrf2/HO-1 pathwayand its mechanism

目的 研究阿托伐他汀通过核因子E2相关因子2(Nrf2)/血红素氧合酶-1(HO-1)改善慢性心力衰竭(CHF)大鼠心功能的作用及机制研究。方法 将成年SPF级雄性SD大鼠随机分为假手术(SHAM)组、CHF组、阿托伐他汀组、二甲基亚砜(DMSO)+SHAM组、DMSO+CHF组、DMSO+阿托伐他汀组、Nrf2抑制剂(ML385)+阿托伐他汀组,每组各8只大鼠。采用腹主动脉缩窄法建立CHF模型或进行假手术操作,造模后给予10 mg/kg阿托伐他汀、30 mg/kg Nrf2抑制剂ML385或等体积的DMSO溶剂灌胃干预。给药8周后采用超声仪检测各组大鼠心功能参数左室射血分数(LVEF)、左室短轴缩短率(LVFS)、左心室舒张末期内径(LVEDD),左心室收缩末期内径(LVESD),观察心脏大体形态并检测心脏质量、心脏体质量比,取左心室心肌组织检测丙二醛(MDA)、8-羟基脱氧鸟嘌呤(8-OHdG)、总抗氧化力(T-AOC)的水平及Nrf2、HO-1的表达。结果 腹主动脉缩窄法造模后,CHF组的LVEDD、LVESD、心脏质量、心脏体质量比及心肌中MDA、8-OHdG的水平均高于SHAM组,LVEF、LVFS、心肌中T-AOC水平及Nrf2、HO-1表达水平均低于SHAM组(P<0.05);经阿托伐他汀干预后,阿托伐他汀组的LVEDD、LVESD、心脏质量、心脏体质量比及心肌中MDA、8-OHdG的水平均低于CHF组,LVEF、LVFS、心肌中T-AOC水平及Nrf2、HO-1表达水平均高于CHF组(P<0.05);阿托伐他汀干预的同时给予Nrf2抑制剂ML385,ML385+阿托伐他汀组的LVEDD、LVESD、心脏质量、心脏体质量比及心肌中MDA、8-OHdG的水平均高于DMSO+阿托伐他汀组,LVEF、LVFS、心肌中T-AOC水平及Nrf2、HO-1表达水平均低于DMSO+阿托伐他汀组(P<0.05)。结论 阿托伐他汀对CHF大鼠的心功能具有改善作用,这一作用可能与激活Nrf2/HO-1通路、减轻氧化应激反应有关。

Objective To study the effect of atorvastatin on improving cardiac function of rats with chronic heart failure(CHF) through Nrf2/HO-1 pathwayand its mechanism.Methods Adult male SD rats were randomly divided into SHAM group,CHF group,atorvastatin group,DMSO+SHAM group,DMSO+CHF group,DMSO+atorvastatin group and ML385+atorvastatin group.The CHF model was established by abdominal aortic constriction or sham operation.After modeling,10 mg/kg atorvastatin,30 mg/kg Nrf2 inhibitor ML385 or equal volume of solvent DMSO was administered by gavage.After eightweeks of administration,left ventricular ejection fraction(LVEF),left ventricular short axis shortening(LVFS),left ventricular end diastolic diameter(LVEDD) and left ventricular end systolic diameter(LVESD) were measured by ultrasound.The general morphology of the heart was observed and the heart weight and heart body weight ratio were measured.The left ventricular myocardial tissue was taken and the level of malondialdehyde(MDA),8-hydroxydeoxyguanine(8-OHdG),total antioxidant capacity(T-AOC) and the expression of Nrf2 and HO-1 were measured.Results The levels of LVEDD,LVESD,heart weight and heart body weight ratio,the levels of MDA and 8-OHdG in myocardium of CHF group were higher than those of sham group,and the levels of LVEF,LVFS,the level of T-AOC,the expression of Nrf2 and HO-1 in myocardium of CHF group were lower than those of sham group(P<0.05).After atorvastatin intervention,the levels of LVEDD,LVESD,heart weight and eart body weight ratio,the levels of MDA and 8-OHdG in myocardium of atorvastatin group were lower than those of CHF group,and the levels of LVEF,LVFS,the level of T-AOC,the expression of Nrf2 and HO-1 in myocardium were higher than those in CHF group(P<0.05).Atorvastatin intervention was accompanied by Nrf2 inhibitor ML385,the levels of LVEDD,LVESD,heart weight and heart body weight ratio,the levels of MDA and 8-OHdG in myocardium of ML385+atorvastatin group were higher than DMSO+atorvastatin group,and the levels of LVEF,LVFS,the level of T-AOC,the expression of Nrf2 and HO-1 in myocardium were lower than those of DMSO+atorvastatin group(P<0.05).Conclusions Atorvastatin can improve cardiac function of CHF rats,which is related to the activation of Nrf2/HO-1 pathway and then the reduction of oxidative stress.