沙库巴曲缬沙坦对心肌梗死后心力衰竭大鼠的心脏保护机制探讨

目的 探究沙库巴曲缬沙坦对心肌梗死后心力衰竭大鼠的心脏保护作用机制。方法 成年雄性SD大鼠60只按随机数字表法均分为对照（Control）组、模型组、沙库巴曲缬沙坦（ARNI）组。通过结扎左冠状动脉前降支构建心力衰竭模型，其中Control组仅穿线但不结扎，其余2组结扎后分别给予生理盐水、沙库巴曲缬沙坦（68 mg/kg）进行灌胃。3个月后超声心动图检查左心室舒张末期内径（LVEDD）、左心室收缩末期内径（LVESD）、左心室舒张末期容积（LVEDV）、左心室短轴缩短分数（LVFS）和左心室射血分数（LVEF）。苏木精-伊红（HE）染色、Masson染色和天狼猩红染色明确心肌结构、纤维化以及胶原分布情况，酶标仪检测血浆炎症氧化应激相关指标，Western blot检测B淋巴细胞瘤-2基因（Bcl-2）、Bcl-2相关的X蛋白（Bax）、半胱氨酸蛋白酶-3（Caspase-3）、凋亡相关因子（Fas）和凋亡相关因子配体（FasL）蛋白表达情况。结果 与Control组相比，模型组LVEDV、LVEDD、LVESD、IL-2、IL-6、TNF-α、Bax、Caspase-3、Fas和FasL表达水平增加，LVEF、LVFS、SOD、GST、IL-10和Bcl-2表达水平降低，心肌细胞坏死增加，胶原生成和纤维化加剧。ARNI组相较于模型组，左心室重构明显减轻，LVEF和LVFS上升，心肌细胞坏死减少，纤维化减轻，IL-2、IL-6、TNF-α、Fas和FasL表达减少，GST、IL-4、IL-10和Bcl-2表达增加（P<0.05）。结论 沙库巴曲缬沙坦通过下调Bax、Fas和FasL蛋白，减少心肌细胞凋亡，减轻氧化应激、炎症反应和心肌纤维化，减轻左心室重构。

Study on the cardioprotective mechanism of sacubitril and valsartan in post-myocardial infarction heart failure of rats

Objective To investigate the mechanism of cardioprotective effect of sacubitril/valsartan (ARNI) on heart failure rats after myocardial infarction. Methods A total of 60 adult male rats were randomly divided into the control group, the model group and the ARNI group. The model of heart failure was established by the ligation of of anterior descending branch of left coronary artery, while in the control group, threaded was inserted without ligation. The other two groups were given normal saline and ARNI (68 mg/kg) by gavage after ligation. After 3 months, echocardiography was completed to measure left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular end diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF). Hematoxylin and eosin (HE) staining and Masson staining were used to determine the myocardial structure and fibrosis. Enzyme linked immunosorbent assay (ELISA) was used to detect related indicators of inflammation and oxidative stress. Western blot assay was used to detect the expression levels of Bcl-2, Bax, Caspase3, Fas and FasL proteins. Results Compared with the control group, values of LVEDD, LVESD, LVEDV, IL-2, IL-6, TNF-α, Bax, Caspase-3, Fas and FasL were increased, but LVEF, LVFS, SOD, GST, IL-10 and Bcl-2 were decreased in the model group. Myocardial cell necrosis obviously increased, collagen production and fibrosis intensified in the model group. The application of ARNI reduced left ventricular remodeling and increased LVEF and LVFS, decreased inflammation and fibrosis, and decreased expression levels of IL-2, IL-6, TNF-α, Fas and FasL, and increased the expression levels of GST, IL-4, IL-10 and Bcl-2 (P<0.05). Conclusion Sacubitril/valsartan can reduce myocardial cell apoptosis, reduce oxidative stress, inflammatory response and fibrosis by down-regulating Bax, Fas and FasL proteins, and reducing left ventricular remodeling to preserve LVEF.