| Objective: Based on the multi-target regulation characteristics of nuclear transcription factor LXR,the effect and mechanism of Mufangji decoction on right heart failure caused by pulmonary hypertension were explored from the aspects of improving cardiac function and regulating water metabolism,so as to provide scientific basis for the treatment of right heart failure and enrich the modern scientific connotation of Zhiyin.Methods: A right heart failure of pulmonary hypertension model was established by monocrotaline injection into rats,then divided into blank control group,model group,low-dose Mufangji decoction group,high-dose Mufangji decoction group and furosemide control group.The corresponding interventions were implemented respectively.(1)General conditions of rats were observed and recorded.(2)Echocardiographic detection of pulmonary artery pressure related indicators:pulmonary artery pressure(P),pulmonary artery pressure to velocity ratio(P / V),pulmonary artery blood flow acceleration time(PA-AT)and pulmonary artery blood flow Acceleration time to ejection time ratio(PA-AT / ET).(3)Heart ultrasound detection: heart rate(HR),cardiac output(CO),stroke volume(SV),ejection fraction(EF),right ventricular internal diameter(RV),right atrium inner diameter(RA),diastolic left ventricular inner diameter(LVIDd),systolic left ventricular inner diameter(LVIDs),end-diastolic volume(EDV)and left ventricular short axis shortening rate(FS).(4)Serum neuroendocrine factor levels(including BNP?Ang II?Ren)were detected by ELISA.(5)Pathological morphological changes of rat heart and kidney tissue were detected by using HE staining;myocardial fibrosis changes in rats was detected by Masson staining.(6)The expression of AQP2 in renal collecting duct was measured by immunohistochemistry.(7)TUNEL staining was used to detect the apoptosis of rat cardiomyocytes.(8)Western blot and RT-PCR were used to detect the protein and m RNA levels of LXR ?,NF-?B and TNF-? in cardiac tissues.(9)SPSS22.0 software was used for multi-factor difference analysis of data.Results:(1)General condition: compared with the blank control group,the model group showed poor spirits,slow reaction,fur color of dark and gloomy,shortness of breath,less food,reduced stool and urine,and effusion in the chest and abdomen.After the intervention,the mental state,food intake,fur color,breathing,hydrothorax and seroperitoneum,defecating frequency and feces traits of rats were significantly improved,especially in the high-dose Mufangji decoction group.(2)Pulmonary artery pressure: compared with the blank control group,the pulmonary artery pressure(P),pulmonary artery pressure to velocity ratio(P / V),pulmonary artery blood flow acceleration time(PA-AT)and pulmonary artery blood flow Acceleration time to ejection time ratio(PA-AT / ET)of model group was significantly changed(P<0.05),which suggested that the right heart failure model of pulmonary hypertension was established successfully.Compared with the model group,Mufangji decoction high-dose group and furosemide control group were significantly improved in pulmonary artery pressure(P)(P <0.01);pulmonary artery pressure and velocity ratio(P/V),pulmonary artery blood flow acceleration time(PA-AT)and the ratio of pulmonary artery blood flow acceleration time to ejection time(PA-AT/ET)were significant increased in Mufangji decoction high-dose group(P <0.05),which were better than that in furosemide control group.(3)Cardiac ultrasound detection:compared with the blank control group,the right atrium inner diameter(RA)and right ventricular internal diameter(RV)were significantly increased in the model group(P< 0.001),the diastolic left ventricular inner diameter(LVIDd)was also increased(P<0.05).The systolic left ventricular inner diameter(LVIDs)and end-diastolic volume(EDV)compared with blank control group were increased too(P<0.01).Compared with the model group,the stroke volume(SV)of high-dose Mufangji decoction group and furosemide control group were significantly increased(P<0.01),the low and high dose groups of Mufangji decoction were significantly increased in the stroke volume(SV)and atrium inner diameter(RA)(P <0.001),and the low dose groups of Mufangji decoction and furosemide control group were significantly decreased in EDV(P<0.05).(4)Serum neuroendocrine factors : ELISA results showed that compared with blank control group,the model group was increased in BNP,angiotensin II(P <0.05)and the level of renin(P<0.01).The low-dose group of Mufangji decoction and furosemide control group was reduced in the levels of BNP,angiotensin II and the level of renin(P <0.05),compared with model group.(5)Myocardial histopathological results: compared with the blank group,myocardial fibers in the model group showed autolysis,broken,curled,disordered arrangement,pyknosis of myocardial nucleus,infiltration of lymphocytes and macrophages;compared with the model group,the muscle fibers of each drug intervention group were arranged orderly,lymphocyte infiltration was significantly reduced,and myocardial nuclear pyknosis and rupture were reduced.The improvement was more significant in the high-dose group of Mufangji decoction.Masson staining results showed that compared with the blank control group,myocardial interstitial fibrous tissue and collagen deposition in the model group was significantly increased.Compared with the model group,the collagen deposition of myocardial interstitial fiber in each drug intervention group was reduced to varying degrees.(6)Renal histopathological results: The results of HE staining showed that compared with the blank group,glomerular injury,volume reduction,partial epithelial swelling,necrosis and shedding of renal tubules were observed in the model group.Compared with the model group,the structure of glomeruli and renal tubules in the drug intervention groups were improved to varying degrees,and the swelling and necrosis of renal tubular epithelium were significantly reduced.(7)Immunohistochemical results:compared with the blank group,the expression of AQP2 in kidney tissue of model group was significantly reduced(P<0.05);compared with model group,the expression of AQP2 positive cells in kidney tissue of high-dose Mufangji decoction group was increased(P <0.01).(8)TUNEL staining results: compared with the blank group,the apoptosis of myocardial cells in the model group was significantly increased(P< 0.001),while in in the high-dose Mufangji decoction group,it was significantly decreased(P < 0.001).(9)The expression of LXR?,NF-?B and TNF-?in myocardial tissue: the results of q RT-PCR showed that compared with the blank control group,the expression of LXR ? m RNA in the model group was decreased,and the expression of NF-? B m RNA and TNF-? m RNA in the model group wasincreased in the control group;compared with the model group,the expression of LXR ? m RNA was increased and the NF-? B m RNA and TNF-? m RNA was decreased in the high and low dose groups of Mufangji decoction,but with no significant difference(P > 0.05).Western blot test showed that theexpression of LXR? was significantly decreased,and the expression of NF-? B and TNF-? was increased in model group than that in blank control group(P < 0.001).Compared with the model group,the expression of LXR ? protein in the high dose group(P < 0.01)and the low-dose group(P < 0.05)was increased,the expression of NF-? B protein and TNF-? protein in the low-dose group and high-dose group of Mufangji decoction was decreased(P < 0.001).Conclusions:1.In this study,monocrotaline was used to successfully replicate the right heart failure model of pulmonary hypertension in rats,which was consistent with the pathophysiological characteristics of cardiovascular circulation in acute exacerbation of chronic right heart failure.2.Mufangji decoction improved the cardiac function,reduced the pulmonary hypertension,improved the damage and fibrosis of cardiac tissue,and the pathological damage of renal.Meanwhile,it also regulated the level of BNP and the renin angiotensin.The overall effect was better than that of furosemide.3.Mufangji decoction reduces the cardiomyocyte apoptosis,myocardial fibrosis and ventricular remodeling by up-regulating the expression of LXR ? protein,which in turn inhibited the expression level of NF-?B,and reduced the expression of downstream TNF-?,to achieve the therapeutic effect of heart failure. |
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