摘要
目的:研究早期应用沙库巴曲缬沙坦(Sacubattril/Valsartan,SAC/VAL)对自发性高血压大鼠急性心肌梗死(acute myocardial infarction,AMI)再灌注心脏重构及心功能的影响.方法:选取60只自发高血压大鼠.随机分为对照组(n=10)和实验组(n=50).采取结扎冠状动脉的方法建立AMI大鼠再灌注模型;实验组大鼠随机分为三组,分别术后给予安慰剂(Model);预防性给予SAC/VAL与VAL;治疗性给予SAC/VAL与VAL.术后连续观察10周,以ELisa酶联免疫吸附法检测hs-TnT、NT-proBNP、TNF-α、IL-2、IL-6和IL-10等表达水平,以超声心动图测定大鼠LVEDD、LVESD、左心室舒张末容积(left Ventricular end-diastolic volume,LVEDV)、左心室收缩末容积(left ventricular end systolic volume,LVESV)、左心室短轴缩短率(fraction shortening,FS)及 LVEF;10周后处死大鼠并以苏木素伊红(HE)染色,Masson染色,并计算胶原容积分数(collagen volume fraction CVF);用Western blot分析法测定心肌组织中p-NF-κB、p-IκB的蛋白水平.结果:①与Sham组比较,实验各组大鼠心肌细胞肥大、排列紊乱、纤维化明显,CVF显著升高(P＜0.01);hs-TnT、NT-proBNP、TNF-α、IL-2、IL-6表达水平明显升高(P＜0.01),IL-10表达水平明显下降(P＜0.01);超声心动图测定心脏扩大且收缩功能显著受损(P＜0.01).②与Model组比较,用药各组梗死交界区心肌细胞结构相对完整,肌间隙变窄,CVF显著下降(P＜0.01);hs-TnT、NT-proBNP、TNF-α、IL-2、IL-6 水平明显降低(P＜0.01),IL-10 表达水平明显升高(P＜0.01);LVEDD、LVESD、LVEDV、LVESV 明显下降(P＜0.05),FS、EF 值明显增加(P＜0.01).③在两组治疗方案中,SACNAL和VAL均可改善AMI后大鼠心功能,但SAC/VAL提供了更好的心功能保护,差异具有统计学意义(P＜0.01).④P-SAC/VAL组与T-SACNAL组比较,CVF减小更加明显,hs-TnT、NT-proBNP、TNF-α、IL-2、IL-6水平明显降低(P＜0.01),IL-10表达水平明显升高(P＜0.01),LVEDD、LVESD、LVEDV、LVESV 明显下降(P＜0.01),FS、EF 值明显增加(P＜0.01).⑤与Model组比较相比,治疗组心肌组织中磷酸化核因子κ B(phosphorylated nuclear factorkappa B,p-NF-κB)、磷酸化 κB 抑制蛋白(phosphorylated inhibitor of kappa B,p-IκB)表达下调(P＜0.05).结论:①SAC/VAL或VAL在AMI再灌注后均可有效改善心室重构、心功能;②与VAL相比,SAC/VAL在预防及治疗AMI诱导的心功能障碍方面效果更佳;③SAC/VAL早期预防性应用可更好地改善心功能.④SAC/VAL可能通过下调p-NF-κB、p-IκB蛋白表达发挥保护心功能的作用.此获益可能与SACNAL抑制心肌炎症反应,抑制细胞凋亡,减轻心肌纤维化,改善左心室重构相关.
Abstract
Objective:To study the effects of Sacubattril/Valsartan(SAC/VAL)on cardiac remodeling and cardiac function in spontaneously hypertensive rats with acute myocardial infarction(AMI)reperfusion.Methods:A total of 60 spontaneously hypertensive rats were randomly divided into control group(n=10)and experimental group(n=50).Control group was the sham operation group,experimental group included the model group,the prophylactic group and the treatment group,the latter two which included SAC/VAL subgroup and VAL subgroup.Results:Compared with the sham group,cardiomyocytes were hypertrophic and fibrotic in all experimental groups,CVF was significantly increased(P＜0.01);The five cytokines(hs-TnT,NT-proBNP,TNF-α,IL-2 and IL-6)were significantly increased(P＜0.01),while the IL-10 was significantly decreased(P＜0.01).echocardiography determined that the heart was enlarged and significantly impaired in systolic function(P＜0.01).Compared with model group,the cardiomyocytes were relatively complete and CVF was significantly decreased(P＜0.01).Compared with VAL,SAC/VAL provided better protection of cardiac function,the difference was statistically significant(P＜0.01).Compared with T-SAC/VAL group,the P-SAC/VAL group showed better improvement in cardiac function and lower pro-inflammatory factors.The expression of p-NF-κB and p-IκB protein was downregulated in the myocardial tissue compared with the Model group(P＜0.05).Conclusion:SAC/VAL or VAL can effectively improve ventricular remodeling and cardiac function induced by AMI.Compared with VAL,SAC/VAL is more effective in preventing and treating cardiac dysfunction induced by AMI;The early application SAC/VAL can better improve cardiac function.SAC/VAL may play a protective cardiac function by downregulating phosphorylated nuclear factorkappa B(p-NF-κB),phosphorylated inhibitor of kappa B(p-IκB)protein expression.This benefit of SAC/VAL is likely to be related to inhibit myocardial inflammatory response,inhibiting cell apoptosis,alleviating myocardial fibrosis and improving left ventricular remodeling.
维普
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