黄芪甲苷通过RNF10-NF-κB途径改善小鼠心梗后心室重构的机制研究

AstragalosideⅣImproves Ventricular Remodeling in Acute Myocardial Infarction Mice through RNF10-NF-κB Pathway

目的:研究黄芪甲苷(AS)对急性心肌梗死(AMI)小鼠心室重构的作用及机制。方法:手术构建AMI心室重构小鼠模型。根据饮食不同,将60只小鼠平分为对照组、模型组、AS低剂量组(40mg/kg)、AS高剂量组(80mg/kg)。记录各组小鼠2周内心脏破裂发生率及心脏重构相关超声指标。Real-time分析心脏重构相关基因[基质金属蛋白酶(MMP)-2,9,金属蛋白酶抑制因子-2(TIMP-2)]、炎症基因[白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、血管细胞黏附分子-1(VCAM-1)]及环指蛋白10(RNF10)-P65关键信号基因的表达,并比较组间差异。结果:各组小鼠心脏破裂发生率无统计学差异(P>0.05)。心脏超声提示AS能减轻心脏扩大、改善室壁变薄、增加心肌收缩(P<0.05)。AS高剂量组在局部室壁形态上改善更为明显(P<0.05)。Real-time PCR结果提示模型组MMP-2、MMP-9表达上升(P<0.05),TIMP-2表达下降(P<0.05);心肌炎症基因(IL-6、TNF-α、VCAM-1)表达升高(P<0.01);关键信号基因RNF10明显下调(P<0.01),P65显著升高(P<0.01)。AS干预后所有基因表达均得到逆转(P<0.05),其中AS高剂量组逆转效果更好(P<0.05)。结论:AS能改善AMI心脏重构,可能与其能调控RNF10-NF-κB途径,影响心肌炎性因子释放及抑制MMP活性有关。

Objective: To study the effects and the molecular mechanism of astragaloside Ⅳ on ventricular remodeling in mice with acute myocardial infarction (AMI). Method: In the experiment, a mouse model of AMI ventricular remodeling was constructed by surgery. 60 mice were equally divided into four groups according to the different diet: control group, model group, low dose group (40mg/kg, astragaloside Ⅳ), high dose group (80mg/kg, astragaloside Ⅳ). The incidence of cardiac rupture within 2 weeks was recorded, and the morphological indicators related to cardiac remodeling were detected by ultrasound. The expressions of the inflammation genes (IL-6, TNF-α, VCAM-1), the remodeling gene (MMP-2,9,TIMP-2) and the key signal transduction genes (RNF10, P65) in myocardium were analyzed by Real-time PCR. Results: There was no significant difference in the cardiac rupture incidence among the groups ( P >0.05). Echocardiography showed that Astragaloside Ⅳ can reduce heart enlargement,enhance myocardial contraction, and reduce ventricular wall thinning ( P <0.05). Among them, the high-dose group was more effective in improving local ventricular wall morphology ( P <0.05). Real-time PCR suggested that the expressions of MMP-2,9 in the model group were significantly increased ( P <0.05), while the expressions of TIMP-2 were decreased ( P <0.05);The expressions of myocardial inflammation genes (IL-6, TNF-α, VCAM-1) were up-regulated ( P <0.01);The key signal transduction gene RNF10 was down-regulated ( P <0.01) and p65 mRNA was significantly increased ( P <0.01). However, these changes were attenuated after astragaloside Ⅳ treatment showing a dose related( P <0.05). Conclusion: Astragaloside Ⅳcould improve cardiac remodeling. This effect may be closely related to the regulation of RNF10-NF-κB pathway-mediated inflammation and the inhibition of matrix metalloproteinase activity.