| According to the survey in recent years the incidence of acute myocardial infarction(AMI)climbed seriously threatened the human health,Ventricular remodeling(VR)is the compensatory response,that heart itself to maintain effective cardiac function after the occurrence of AMI,and it is a reconstruction process of morphology and structure of the ventricular wall for repairing the pathological change,but continuous ventricular remodeling can cause the change of cardiac structure and function,and make the function of heart pump lowly,cardiac decompensate resulting heart failure and death finally.The progressive deterioration of cardiac performance is the main pathological process and an important warning sign of cardiovascular events eventually developing heart failure,and also its mechanism is complex and multivariate.Therefore,how to improve or delay the VR is a key link of cannot be ignored in the process of prevention and treatment of heart failure.In recent years,traditional Chinese medicine treatment of heart disease showed advantages and broad prospect in many aspects,and has obtained certain clinical effect from the aspects of warming yang,tonifying qi and invigorating the circulation of blood.Paeonol(Pae)is a class of small molecules phenolic compounds,separated from dry skin of root and dry stem of Ranunculaceae Peony and Asclepiadaceae Cynanchum paniculatum,it can protect myocardial tissue and prevent atherosclerosis throughing the pharmacological action of reducing the myocardial oxygen consumption,inhibiting the platelet aggregation,improv-ing blood circulation,increasing coronary blood flow.Our previous research has shown that Pae has very good effect to inhibit ventricular remodeling and improve cardiac function after myocardial infarction rats.Panax Notoginseng Saponins(PNS)is the main active Ingredient of Araliaceae pseudo-ginseng,its pharmacological action is wide,such as antihypertensive effects,vasorelant,anticoagulation and reducing the myocardial oxygen consumption,and so on.Research has shown that PNS can inhibit lipid peroxidation to slow ventricular remodeling after myocardial infarction rats.Both of the active ingredients is used solely to protecting the cardiovascular system after myocardial infarction rats,but according to the basic theory of traditional Chinese medicine of compatibility of traditional Chinese medicine using,there is no report about whether combination of both has the synergy in treating diseases.This experiment by observing the effects on ventricular remodeling after myocardial infarction rats and its mechanism of the combination,provides powerful experimental basis for developing Pae and PNS into new drug about preventing and treating ventricular remodeling after myocardial infarction.Objectives:To investigate the effects and molecular mechanism of Paeonol combined with PNS on ventricular remodeling after acute myocardial infraction rats and discuss its related.Methods:In this study,80 healthy male Sprague-Dawley(SD)rats [SPF level,body weight(200±20)g ],feed by basal feed after one week,randomly selected 70 were subjected to ligation on Left Anterior Descending(LAD)artery to establish AMI model.According to the ST segment in ecg arch elevated more than 1/2 as a successfully established standard of AMI model,3 days later,live rats were tested by electrocardiogram again,to display Alive modle rats were divided into model group,Pae group(8 mg·kg-1),PNS group(40 mg·kg-1),Low-dose combination group(Pae 4 mg·kg-1 + PNS 20 mg·kg-1),High-dose combination group(Pae 8 mg·kg-1 + PNS 40 mg·kg-1)and captopril group(10 mg·kg-1)positive contrast group by random allocation according to different interventions,another 10 rats were sham group,which only in the left anterior descending coronary artery same location thread not ligation.Each treatment group rats by intraperitoneal injection once a day were given corresponding drugs,model group and sham group were given amount of normal saline as the same way for 28 d.After intervention 28 d,detecte the hemodynamic parameters in each group,determinate left heart index of each group rats,Haematoxylin and Eosin(HE)staining and Masson trichrome were conducted to observe cardiac morphological pathology changes and the degree of myocardial fibrosis,RT-PCR assay was conducted to detecte the mRNA expression of NF-?B p65,TNF-? and IL-1?,Western blot was conducted to detecte the protein expression levels of NF-?B p65,p-I?B? and TNF-? in myocardium.Results:1 Effect on hemodynamics The LVSP value and ± dp/dtmax value of model group are lower than sham group,but LVEDP value is higher(P < 0.01),it indicated that myocardial diastolic ability is asthenia and cardiac function was damaged badly after AMI.Compared with model group,the value of LVSP and ± dp/dtmax were improve in each intervention group and LVEDP value was descending obviously(P < 0.01);in addition,the situation of the indexs improved in the combination groups were better than single medicine group(P < 0.01);and High-dose combination group was much better than Low-dose combination group(P < 0.05).2 Impact on left ventricular mass index(LVMI)The LVMI of model group rats(0.34 ± 0.01)was higher than sham group rats(0.21 ± 0.02)(P < 0.01);compared with model group,the LVMI of each intervention group were reduced in varying degrees(P < 0.01);the LVMI of combination groups compared with Pae group(0.30 ± 0.01)and PNS group(0.29 ± 0.02)was reduced obviously(P < 0.01),High-dose combination group(0.24 ± 0.01)was more obviously than Low-dose combination group(0.26 ± 0.02)(P < 0.01).3 The results of HE staining Tissue was observed by optical microscope,the myocardial tissue was normal in sham rats;the cardiac muscle fibreof rats in the model group arranged disorder including fracture,dissolution,necrosis and inflammatory cells infiltrated and in connective tissue proliferated severely,cell space widened,organization loose,cardiomyocytes hypertrophy and uneven dyeing,cell nuclear pyknosis,fragmentation,or even disappear,suggested that the VR model rats was successfully established after AMI.Obtain that the myocardial pathologic structure had varing degrees improvement in the intervention groups compared with the model group by observing that complete myocardial fibers lined up and inflammatory infiltrates reduced,cell morphology tended to be the norm,dyeing was symmetrical roughly.Especially the High-dose combination group improved more significantly than Low-dose combination group.4 Masson staining results Observed by optical microscope,the collagen fibers stained blue,muscle were stained red and nuclei were bluish brownness,there was no obvious pathological change in sham group.The collagen fibers connective tissue was serious hyperplasia to form network and arrangement disorder,scar formation and myocardial collagen tissue increased significantly in model group.Compared with the model group,the myocardial pathologic changes had varing degrees improvement,there was no lots of connective tissue,scar,and collagen tissue decreased with different extent in each administration group by macroexamination.Compared with single herbs groups,the myocardial collagen tissue of combination decreased significantly,especially in the High-dose combination group,insinuated that the drugs can improve MF variously.5 Cardiac gene expression by RT-PCR Compared with sham group,the mRNA levels of NF-?B p65,TNF-? and IL-1? were up-regulated significantly in model rats myocardium(P < 0.01);compared with model group,the administration of durgs groups showed varying degrees down-regulated for the gene expressions(P < 0.01);significantly reduce with combination groups(P < 0.05,P < 0.01)and High-dose combination group was lower than Lowdose combination group(P < 0.05,P < 0.01).6 Proteins expression by Western blotting Compared with sham group,NF-?B p65,p-I?B? and TNF-? proteins were enhanced after coronary ligature four weeks(P < 0.01),but they were varying degrees suppressed by the administration of durgs significantly(P < 0.01);the proteins for combination groups were reduced evidently(P < 0.05,P < 0.01),and High-dose combination group was more significantly.Conclusions:1 The combination of Pae and PNS can inhibit the changes of myocardial cell morphology and the degrees of myocardial fibrosis after rats myocardial infarction to delay ventricular remodeling and also play obvious synergistic action.2 The combination of Pae and PNS can strengthen cardiac function and improve ventricular remodeling by reducing LVMI and LVEDP value,but improving LVSP and ± dp/dtmax value,and also play obvious synergistic action.3 The combination of Pae and PNS can reduce the expressions of NF-?B p65 and p-I?B? in ventricular remodeling rats after myocardial infarction,further inhibit the excessive activation of NF-?B/I?B inflammatory signaling pathways.4 The molecular mechanism of Pae combined whit PNS inhibited or delayed ventricular remodeling may relate with interrupting NF-?B/I?B signaling pathways and down-regulating the expressions of TNF-? and IL-1? to reduce inflammation.5 The combination of Pae and PNS can improve the ventricular remodeling after myocardial infarction,and show up obvious synergy. |
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