沙库巴曲缬沙坦调控RhoA/ROCK信号通路对慢性心力衰竭心室重构的影响研究

Effect of Sacubitril/Valsartan on RhoA-ROCK Signaling Pathway to Ventricular Remodeling in Rats with Chronic Heart Failure

目的:分析沙库巴曲缬沙坦对慢性心力衰竭(CHF)动物模型RhoA/ROCK信号通路的调控以及对心室重构的影响效应。方法:将45只SD大鼠随机分成3组:空白组(予以生理盐水)、模型组(予以阿霉素腹腔注射制备CHF大鼠模型)和治疗组(予以CHF大鼠60 mg/kg沙库巴曲缬沙坦灌胃4周),每组15只。比较3组大鼠左心室射血分数(LVEF)、左心室舒张末期内径(LVEDD)、室间隔厚度(IVST)、左心室心肌质量指数(LVMI)等心脏结构指标以及血浆N末端脑钠肽前体(NT-proBNP)、基质金属蛋白酶9(MMP-9)、半乳糖凝集素3(Gal-3)水平。比较3组大鼠心肌组织形态学以及心肌胶原沉积程度。比较3组大鼠心肌组织RhoA及ROCK m RNA以及蛋白表达水平差异。结果:空白组大鼠LVEF最高,且治疗组大于模型组(P<0.05);空白组大鼠LVEDD、IVST、LVMI最低,且治疗组小于模型组(P<0.05)。空白组大鼠NT-proBNP、MMP-9及Gal-3最高,且治疗组大于模型组(P<0.05)。模型组心肌细胞增大,排列紊乱,心肌胶原沉积显著大于治疗组。空白组大鼠RhoA及Rock m RNA及蛋白水平最低,且治疗组低于模型组(P<0.05)。模型组及治疗组大鼠RhoA及Rock m RNA以及蛋白的表达与LVEDD、IVST、LVMI、NT-proBNP、MMP-9及Gal-3呈正相关,与LVEF呈负相关(P<0.05)。结论:沙库巴曲缬沙坦通过靶向负调控RhoA/ROCK信号通路影响CHF心室重构程度。

Objective:To analyze the regulation of sacubitril/valsartan to the RhoA-ROCK signaling pathway in rat with chronic heart failure(CHF),and the effect of ventricular remodeling.Methods:A total of 45 SD rats were divided into 3 groups randomly,which were control group(injected normal saline),model group(made CHF rat model by peritoneal injection with Adriamycin)and therapy group(intragastric administration sacubitril/valsartan with 60 mg/kg 4 weeks to CHF rats).Each group had 15 rats.The cardiac function indexes of left ventricular ejection fraction(LVEF),left ventricular end diastolic diameter(LVEDD),interventricular septal thickness(IVST),left ventricular mass index(LVMI)and the plasma levels of N-terminal pro-brain natriuretic peptide(NT-proBNP),matrix metalloproteinase-9(MMP-9),Galectin-3(Gal-3)were compared among 3 groups.The cardiac histomorphology indexes and degree of myocardial collagen deposition were detected and compared among 3 groups.The expression levels of RhoA and ROCK in myocardial tissue were compared among 3 groups.Results:The LVEF of rats in control group were highest,and the LVEF of rats in therapy group were higher than in model group(P<0.05).The levels of LVEDD,IVST,LVMI in control group were lowest,and the levels of LVEDD,IVST,LVMI in therapy group were lower than model group(P<0.05).The plasma levels of NT-proBNP,MMP-9,Gal-3 in control group were highest,and the levels of NT-proBNP,MMP-9,Gal-3 in therapy group were higher than model group(P<0.05).The enlarged cardiac cell and disorderly arrangement in model group were observed,and the degrees of myocardial collagen deposition in model group were larger than therapy group.The expression levels of RhoA and ROCK of myocardial tissue were different among 3 groups,which the indexes in control group were the lowest,and the therapy group was the second lowest,and the model group was the highest(P<0.05).The positive relationship of the expression levels of RhoA and ROCK to the levels of LVEDD,IVST,LVMI,NT-proBNP,MMP-9 and Gal-3 were confirmed(P<0.05),and the negative relationship to LVEF was also confirmed(P<0.05).Conclusion:Sacubitril/valsartan has significant negative effect on the ventricular remodeling by the RhoA-ROCK signaling pathway in CHF.