| In recent years, with the deterioration of natural environment, Changes in lifestyle and eating habits, the prevalence of cardiovascular disease isincreasing year by year, its high mortality rate has became one of the main factors threatening people’s lives and health. Ventricular remodeling which leads to heart failure was the cause of death in patients pathological processes. Ventricular remodeling is changes of heart structure and function caused by hypernomic activation of body neural endocrine regulation system and related signal transduction pathway. Mainly show as cardiac ventricular thinning, non infarct zone compensatory hypertrophy, heart enlargement, and myocardial necrosis, scarring and necrotic parts generate compensatory proliferation of fiber, damaging systolic anddiastolic function of theheart, causing hemodynamic changes, eventually leading to heart failure. Over activation of TGF-β/Smads signal transduction pathways after myocardial infarction plays a very important role in ventricular remodeling pathologic process. Therefore, key to the preventing and treating heart failure is to improve and reverses changes of ventricular remodeling of the cardiac morphology and function, and inhibiting the activation of TGF-β/Smads signal transduction pathway is an important starting point.Paeonol which has functions of anti-oxidation and protecting cardio vascular, is extracting from dry skin of Peony root and dry Cynanchumpaniculatum.Paeonol can inhibit platelet coagulation, improve blood circ ulation, increase oronary flow, and reduce myocardial oxygen consumptio n, It can protect heart from myocardial ischemia and atherosclerosis. Wehave proved that paeonol has functions of improve thecardiac function a nd ventricular remodeling,and the molecular mechanism of the functions is TGF-β1-related.Panax Notoginseng Saponins(PNS) which is extracting from dry rhi zome of Panax Notogingseng, has functions of reduce blood press, impr ove myocardial ischemia, improve arrhythmia, improve atherosclerosis.Zh ang XJ have proved that the molecular mechanism of improve ventricul ar remodeling is relate to TGF-β/Smads signal transduction pathway.Paeonol and PNS can protect rat’s cardiovascular with ventricular r emodeling after myocardial infarction, but there is no research on the combination of the two drugs. This experiment is to study on the effect s of the combination on cardiac function and ventricular remodeling in rats with ventricular remodeling after myocardial infarction which establi shed by left coronary artery ligation, and comparing effects of the comb ination with Captopril – effective drug in the clinic, and study effects’molecular mechanism by morphological and molecular biology technolo gy test, and observe if there is a synergistic effect between paeonol andPNS, whichcan provide valuable experimental basis and new idea for d evelopment of the new drug with Paeonol and PNS on the prevention a nd treatment of ventricular remodeling after myocardial infarction.This research points two parts: The first part is to prove there is a synergism effects between Paeonol and PNS of ventricular remodelingafter myocardial infarction by analyze test results of heart function, st ructure, and morphology in rats with ventricular remodeling after myoca rdial infarction. The second part is to study on the molecular mechanis m of the effects by molecular biology technology test. Part 1 Effects of paeonol and PNS combination on heart function and v entricular remodeling after acute myocardialinfraction in ratsObjective:To study on the effects of paeonol and PNS combination on heart function and hemodynamics in rats with ventricular remodeling after acu te myocardialinfraction.Methods:Model of AMI was established by left coronary artery ligation.Rat s without ligation were used as sham operation group. 24 h later,accordin g to the intervention methods, alive rats were divided into model group,paeonol group(8 mg·kg-1) group, PNS group(40 mg·kg-1), paeonol(4mg·kg-1),) + PNS(20 mg·kg-1) formula low dose group, paeonol(8 mg·kg-1),) + PNS(40 mg·kg-1) formula high dose group, and captopri l positive control group(10 mg·kg-1). Sham operation group and model group were given the same amount of normal saline daily by intraperit oneal injection and intragastric administration. Hemodynamic variables an d left ventricular mass index(LVMI) was detected after 28 days treatme nt. HE staining was used to observe changes of myocardial tissue. Mass on staining was used to observe changes of myocardial fibrosis.Results:1 Effects on hemodynamics Compared with sham operation group,model group, paeonol group, PNS group, paeonol + PNS formula low dose group, paeonol + PNS formula high dose group and captopril grou p’ LVSP value decreased obviously(P < 0.01); ± dp/dtmax increased obvi ously(P < 0.01). Compared with model group, paeonol group, PNS gro up, paeonol + PNS formula low dose group, paeonol + PNS formula hi gh dose group and captopril groups’ LVSP value decreased and ± dp/dt max increased obviously. Compared with paeonol group and PNS group, combination groups LVSP value decreased and ± dp/dtmax increased obvi ously. Compared with paeonol + PNS formula low dose group, paeonol+ PNS formula high dose group’s LVSP value decreased and ± dp/dt max increased obviously.2 Effect on left LVMI Compared with sham operation group(0.22±0.01), LVMI of model group(0.31±0.02) increased significantly(P < 0.01); Compared with model groups, LVMI of paeonol group, PNS group, pae onol + PNS formula low dose group, paeonol + PNS formula high dose group and captopril group decrease with differentdegrees(P < 0.01);Compared with paeonol group(0.29±0.02) and PNS group(0.29 ± 0.02),LVMI of combination groups increased significantly(P < 0.01); Compar ed with paeonol + PNS formula low dose group(0.26 ± 0.01), LVMI of paeonol +PNS formula low dose group(0.24 ± 0.02)increased signi ficantly(P < 0.01).3 Results of HE staining Tissues were observed with theoptical mic roscope. Sham operation group showed nothing pathological changes: my ocardial cells were evenly stained, neatly arranged, and clear cytoplasm.Model group showed pathological changes: myocardial cell hypertrophy, karyopyknosis, derangement, cell gap narrowed, intercellular collagen fib er hyperplasia, cell loss, nuclear fragmentation. All treatment groups sho wed obvious improvement in pathological, There was the most significa nt improvement in formulae group and captopril group: cells arranged in neat, cells tend to be normal, uniform staining, no obvious cell hyperpl asia.4 Results of Masson staining Tissues were observed with theoptical microscope.The collagen was blue, myocardial fibers were red and nucl eus were blue black. Sham operation group showed nothing pathologica l changes obviously: Myocardial fibers have slight hyperplasia. Model group showed large amounts of collagen fiber, karyopyknosis, nuclear c ondensation. All treatment groups showed obvious pathological improve ment, and the most significant improvement is in formulae group and captopril group.Conclusion:1 Combination of paeonol and PNS can improve heart function by reduce LVSP and increase LVSP and ± dp/dtmax.2 Combination of paeonol and PNS can improve ventricular remode ling by reducing the degree of myocardial fibrosis after myocardial infar ction in rats to.3 Combination of paeonol and PNS has a seriously synergism effec ts in functions above. Part2 Effects of paeonol and PNS combination on TGF-β/Smads signaltr ansduction pathway in rats with ventricular remodeling after acute myoc ardialinfractionObjective:To study on the effects of paeonol and PNS combination on TGF-β/Smads signal transduction pathway related factors in rats with ventricul ar remodeling after acute myocardialinfractionMethods:The mRNA expression levels of TGF-β1、Collagen Ⅰ、Ⅲ were de tected by RT-PCR technique. The protein expression levels of TGF-β1、Smad2/3 、Collagen Ⅰ、Ⅲ were detected by western blot technique.Results:1 Results of RT-PCR technique: Compared with sham operation gro up, mRNA expression levels of TGF-β1、Collagen Ⅰ、Ⅲin model grou p increased significantly(P < 0.01);Compared with model groups, m RNA expression levels of TGF-β1、Collagen Ⅰ、Ⅲ in treatment group decr eased significantly(P < 0.01); Compared with paeonol group and PNS g roup, mRNA expression levels of TGF-β1、Collagen Ⅰ、Ⅲ in combine d groups decreased significantly(P < 0.01); Compared with paeonol + P NS formula low dose group, mRNA expression levels of TGF-β1 、Coll agen Ⅰ、Ⅲ in paeonol + PNS formula low dose group decreased signi ficantly(P < 0.01).2 Results of Western blotting technique: Compared with sham opera tion group, protein expression levels of TGF-β1、Smad2/3、Collagen Ⅰ、Ⅲin model group increased significantly(P < 0.01);Compared with model groups, protein expression levels of TGF-β1、Smad2/3、Collagen Ⅰ、Ⅲ in treatment group decreased significantly(P < 0.01); Compared withpaeonol group and PNS group, protein expression levels of TGF-β1、S mad2/3、Collagen Ⅰ、Ⅲ in combined groups decreased significantly(P < 0.01); Compared with paeonol + PNS formula low dose group, protei n expression levels of TGF-β1、Smad2/3、Collagen Ⅰ、Ⅲ in paeonol + PNS formula low dose group decreased significantly(P < 0.01).Conclusion:1 Combination of paeonol and PNS can excessive activation of TG F-β/Smads signal transduction pathway by reducing the expression levels of TGF-β1、Smad2/3.2 Combination of paeonol and PNS can reduce the expression lev els of Collagen Ⅰ、Ⅲ by reducing the expression levels of TGF-β1 、S mad2/3 to improve myocardial fibrosis and ventricular remodeling..3 Combination of paeonol and PNS has a seriously synergism effec ts in reducing TGF-β1 and Smad2/3’s expression... |
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