紫檀芪对急性心肌梗死大鼠心肌功能、心肌纤维化和炎症反应的作用及对Notch1/eIF3a信号通路的影响

目的:分析紫檀芪对急性心肌梗死大鼠心肌功能、心肌纤维化和炎症反应的作用及对Notch1/eIF3a信号通路的影响。方法:选取SPF级Wistar雄性大鼠75只,分为5组,紫檀芪低、中、高剂量组在造模前采用紫檀芪溶液预处理,灌胃剂量为10、20及40 mg/kg的紫檀芪溶液;模型组和正常组灌胃等剂量生理盐水。除正常组外,其他大鼠制备急性心肌梗死(AMI)模型。观察大鼠左心室功能、心脏血流动力指标、心肌组织病理形态和纤维化情况、心肌炎症因子含量、eIF3a与Notch1蛋白、mRNA表达。结果:模型组大鼠左室短轴缩短率(LVFS)、左室射血分数(LVEF)较正常组降低,左心室舒张末期内径(LVEDd)、左心室收缩末期内径(LVESd)、收缩末期左室容积(LVESV)和舒展末期左室容积(LVEDV)较正常组升高;紫檀芪低、中、高剂量组大鼠LVFS、LVEF较模型组升高,LVEDd、LVESd、LVESV、LVEDV较模型组降低,差异有统计学意义(P<0.05);模型组大鼠左室压力最大降低速率(－dp/dtmax)、左室压力最大升高速率(＋dp/dtmax)、左心室收缩压(LVSP)较正常组下降,左室舒张末压(LVEDP)较正常组升高;紫檀芪低剂、中、高剂量组大鼠－dp/dtmax、＋dp/dtmax、LVSP较模型组升高,LVEDP较模型组降低,差异有统计学意义(P<0.05);模型组大鼠心肌组织白细胞介素(IL)-6、IL-1β及TNF-α含量较正常组升高;紫檀芪低剂、中、高剂量大鼠心肌组织IL-6、IL-1β及TNF-α含量较模型组降低,差异有统计学意义(P<0.05);模型组大鼠心肌组织eIF3a、Notch1蛋白与mRNA表达较正常组升高;紫檀芪低、中、高剂量大鼠心肌组织eIF3a、Notch1蛋白与mRNA表达较模型组降低,差异有统计学意义(P<0.05)。结论:AMI大鼠心肌炎症和纤维化发展可能和Notch信号通路下游eIF3a表达增加有联系,紫檀芪预处理可明显改善AMI大鼠心室重构,其作用机制可能和抑制eIF3a、Notch1表达有关。

Effects of pterostilbene on myocardial function,myocardial fibrosis and inflammatory response in rats with acute myocardial infarction and on Notch1/eIF3a signaling pathway

AIM: To analyze the effects of pterostilbene on myocardial function, myocardial fibrosis and inflammatory response in rats with acute myocardial infarction and on Notch1/eIF3a signaling pathway. METHODS: Seventy-five Wistar male rats of SPF grade were selected and divided into 5 groups. The low-, medium-, high-dose groups of pterostilbene were pretreated with pterostilbene solution before modeling. The dosage was 10, 20 and 40 mg/kg of the pterostilbene sputum solution, rats of the model group and the normal group were intragastrically administered with the same dose of normal saline; except for the normal group, other rats were prepared with AMI model. The left ventricular function, cardiac blood flow index, myocardial histopathology and fibrosis, myocardial inflammatory factor content, eIF3a and Notch1 protein and mRNA expression were observed. RESULTS: LVFS and LVEF were lower in the model group than in the normal group. LVEDd, LVESd, LVESV and LVEDV were higher than those in the normal group. The LVFS and LVEF in the low, medium and high dose groups of the pterostilbene were higher than those in the model group, LVEDd, LVESd, LVESV, and LVEDV were lower than the model group, and the difference was statistically significant (P<0.05).In the model group, the －dp/dtmax, +dp/dtmax, and LVSP were lower than the normal group, and the LVEDP was higher than the normal group. The －dp/dtmax, +dp/dtmax, and LVSP in the low, medium, and high dose groups of the pterostilbene were increased as compared with model group; while LVEDP was lower than the model group, and the difference was statistically significant (P<0.05).The contents of IL-6, IL-1β and TNF-α in the myocardial tissue of the model group were higher than those in the normal group. The contents of IL-6, IL-1β and TNF-α in the myocardial tissue of rats with low, medium and dose groups of the pterostilbene were decreased as compared with the model group, the difference was statistically significant (P<0.05). The expression of eIF3a and Notch1 protein and mRNA in the myocardial tissue of the model group was higher than that in the normal group. eIF3a, Notch1 protein and mRNA expression in the low-, medium-, and high-dose rat myocardial tissue were lower than the model group, and the difference was statistically significant (P<0.05). CONCLUSION: The development of myocardial inflammation and fibrosis in AMI rats may be associated with the increase of eIF3a expression in the downstream of Notch signaling pathway. Pretreatment of pterostilbene can significantly improve ventricular remodeling in AMI rats, and its mechanism may be related to the inhibition of eIF3a and Notch1 expression.