参连复脉颗粒对大鼠再灌注心律失常的影响及机制研究

Effects of Shenlian Fumai Granule on Myocardial Ischemia Reperfusion Arrhythmia and the Mechanism

目的:探讨参连复脉颗粒对大鼠再灌注心律失常的影响及机制研究。方法:将SD大鼠随机分为模型组、假手术组、美西律组、参连复脉颗粒低剂量组、参连复脉颗粒中剂量组、参连复脉颗粒高剂量组。干预完成后,除假手术组外其余各组大鼠建立心肌缺血再灌注模型;观察各组大鼠心肌缺血再灌注后室性期前收缩(PVC)总个数和心室颤动(VF)+室性心动过速(VT)总时程。进一步检索参连复脉颗粒药物成分,预测成分靶点,同时检索再灌注心律失常靶点,获取药物与再灌注心律失常的交集靶点并筛选核心靶点,借助Metascape平台分析其作用的信号通路。结果:与模型组比较,参连复脉颗粒中、高剂量组PVC总个数和VF+VT总时程均明显下降(P<0.05或P<0.01);与美西律组比较,参连复脉颗粒高、中剂量组VT+VF总时程升高(P<0.05或P<0.01),而参连复脉颗粒高、中剂量组PVC总个数与美西律组比较差异无统计学意义(P>0.05)。筛选得到参连复脉颗粒与再灌注心律失常交集靶点共136个,进一步筛选其核心靶点主要为蛋白激酶B1(AKT1)、肿瘤坏死因子(TNF)、白介素6(IL6)、白介素1β(IL1B)、基质金属蛋白酶9(MMP9)、细胞肿瘤抗原p53(TP53)、丝裂原活化蛋白激酶3(MAPK3)、半胱氨酸蛋白酶3(CASP3)、JUN、环加氧酶2(PTGS2)。这些靶点参与凋亡、磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)和TNF信号通路等与再灌注心律失常密切相关的通路。结论:参连复脉颗粒能降低大鼠再灌注心律失常发生率,其作用可能与美西律类似;网络药理学揭示了参连复脉颗粒预防再灌注心律失常多途径、多靶点的作用特点。

Objective:To investigate the effect of Shenlian Fumai Granule(SLFMKL)on the rat model of myocardial ischemia reperfusion arrhythmia and the mechanism.Methods:The rats were randomly divided into five groups:mexiletine group,low dose of SLFMKL group,middle dose of SLFMKL group,high dose of SLFMKL group,pseudo surgery group,and model control group.After the intervention,myocardial ischemia-reperfusion models were established in all groups except the pseudo surgery group.And then the total number of ventricular premature beats(PVC)and the total duration of ventricular fibrillation(VF)and ventricular tachycardia(VT)after myocardial ischemia-reperfusion were observed in each group.Furthermore,the active components of SLFMKL were retrieved to predict the component targets,and the targets of reperfusion arrhythmia(RA)were retrieved to obtain the intersection targets of drugs and RA,and screen the core targets.The signaling pathways of SLFMKL were analyzed by Metascape platform.Results:Compared with control group,the number of PVC and the duration of VT and VF in high dose of SLFMKL group and middle dose of SLFMKL group were significantly decreased(P<0.05 or P<0.01).Compared with mexiletine group,the total duration of VF and VT was increased(P<0.05 or P<0.01).Compared with mexiletine group,there was no significant difference in the total number of PVC in high dose of SLFMKL group and middle dose of SLFMKL group(P>0.05).A total of 136 intersection targets of SLFMKL and RA were screened,and the core targets were protein kinase(AKT)1,tumor necrosis factor(TNF),interleukin-6(IL6),interleukin-1β(IL1β),matrix metalloproteinase-9(MMP9),tumor protein P53(TP53),mitogen activated protein kinases 3(MAPK3),caspase-3(CASP3),JUN,and cyelooxygenase 2(PTGS2).These targets were involved in pathways closely related to RA,such as apoptosis,phosphatidylinositol 3 kinase(PI3K)-AKT,and TNF signaling pathways.Conclusion:SLFMKL can reduce the incidence of RA in rats,and its effect may be similar to mexiletine.Network pharmacology reveals the multi-pathway and multi-target action characteristics of SLFMKL in the prevention of RA,which provides a basis for subsequent research.