【作者】 吴刚强；

【导师】 郭志华；

【作者基本信息】 湖南中医药大学 ， 中医内科学， 2014， 博士

【摘要】 目的：从Ca2+-CaN-NFAT3信号通路探讨益心泰对慢性心力衰竭家兔心肌重构的作用机理。方法：用阿霉素建立慢性心力衰竭家兔模型,将造模成功的家兔分为模型组、益心泰低、中、高剂量组和氯沙坦钾组；另设正常对照组,共6组。每天上午对家兔进行灌胃,用药组根据成人体表面积换算法,折算后生药量为：益心泰低、中、高剂量组分别按照2.1g/kg、4.2g/kg、8.4g/kg灌胃,氯沙坦钾组按照2.75mg/kg灌胃,模型组和正常组灌服同等体积的生理盐水。1次/d,共用药4周。实验结束后观察血清脑钠肽浓度,心脏超声指标、心肌重构指标以及心肌组织病理结构、心肌超微结构改变；同时从Ca2+-CaN-NFAT3信号通路着手,检测心肌细胞内钙离子浓度,心肌组织CaN的活性,心肌组织NFAT3的蛋白表达及蛋白磷酸化,GATA4及C-Myc的蛋白表达。结果：用药4周后,(1)与模型组比较,各用药组血清BNP水平明显降低(P<0.01)；与低剂量组比较,益心泰中、高剂量组和氯沙坦钾组血清BNP水平明显降低(P<0.01)；(2)与模型组比较,益心泰中、高剂量组和氯沙坦钾组心脏超声指标LVEF、LVFS和E/A明显升高(P<0.01),IVS、LVPW、LVIDs、LVIDd明显下降(P<0.01)；(3)与模型组比较,益心泰中、高剂量组和氯沙坦钾组心脏指数和左心室重量指数明显降低(P<0.01)；与低剂量组比较,益心泰中、高剂量组和氯沙坦钾组心脏指数和左心室重量指数明显降低(P<0.01)；(4)与模型组比较,各用药组心肌细胞内Ca2+明显减少,心肌组织内CaN含量明显降低(P<0.01)；与低剂量组比较,益心泰中、高剂量组和氯沙坦钾组Ca2+和CaN含量明显降低(P<0.05或P<0.01)；(5)与模型组比较,各用药组心肌组织NFAT3、p-NFAT3、 GATA4、C-Myc表达明显下降(P<0.05或P<0.01)；与低剂量组比较,益心泰中、高剂量组和氯沙坦钾组NFAT3、GATA4、C-Myc表达明显降低(P<0.05或P<0.01)；(6)与模型组比较,益心泰中、高剂量组和氯沙坦钾组心肌组织NFAT3mRNA、GATA4mRNA、 C-Myc mRNA表达明显下降(P<0.01)；与低剂量组比较,益心泰中、高剂量组和氯沙坦钾组NFAT3mRNA、 GATA4mRNA、 C-Myc mRNA表达明显降低(P<0.05或P<0.01)；(7)各用药组心肌细胞损伤与模型组比较均有不同程度的减轻。间质炎细胞浸润较模型组减少,水肿也有所减轻。心肌超微结构也较模型组显著改善。结论益心泰能抑制Ca2+-CaN-NFAT3信号传导通路,改善心肌重构,从而改善慢性心力衰竭家兔的心功能。且益心泰中、高剂量组疗效明显优于低剂量组。更多还原

【Abstract】 Objective To investigate the impact and mechanism on the myocardial remodeling of Yi-Xin tai on rabbit with chronic heart failure from Ca2+-CaN-NFAT3signal pathway.Methods Established the rabbit model of chronic heart model with adriamycin,and divided the successful model of rabbit into five groups: model group, high^middle and low dose of Yi-Xin tai groups and Losartan Potassium group, plus the normal control group,6groups in all.Every morning rabbit were given drug according to body surface area method,the conversion of crude drugs are as follows:the low、middle and high dose of Yi-Xin tai group was respectively given2.1g/(kg·d、4.2g/(kg·d) and8.4g/(kg·d), Losartan Potassium group was given2.75g/(kg·d), besides, the model group and normal group were given equally volume of physiological saline.Every rabbit was given only once a day for4weeksAfter the experiment we observed the serum concentration of brain natriuretic peptide,echocardiographic index, index of myocardial remodeling and the changes of myocardial tissue pathological structure and the myocardial ultrastructure, mearsured the concentration of myocardial intracellular calcium ion, the activity of CaN in myocardial tissue, protein expression of NFAT3and phosphorylated NFAT3in myocardial tissue、protein expression of GATA4and C-Myc.Results After4weeks,(1)compared with the model group, the serum levels of BNP of the treatment groups were significantly lower (P<0.01); compared with the low dose group, the levels of BNP of the middle、high dose groups of Yi-Xin tai and Losartan Potassium group were significantly lower(P<0.01);(2) compared with the model group, LVEF、LVFS and E/A of medial、high dose groups of Yi-Xin tai and Losartan Potassium group were significantly higher(P<0.01); IVS、 LVPW、LVIDs、 LVIDd were significantly lower (P<0.01);(3)compared with the model group, the cardiac index and left ventricular mass index of medial、high dose groups of Yi-Xin tai and Losartan Potassium group were significantly lower (P<0.01); compared with the low dose group, the cardiac index and left ventricular mass index of the middle、high dose groups of Yi-Xin tai and Losartan Potassium group were significantly lower (P<0.01);(4) compared with the model group, the concentration of myocardial intracellular calcium ion and the activity of CaN in myocardial tissue of the treatment groups were significantly lower(P<0.01);compared with the low dose group, the concentration of myocardial intracellular calcium ion and the the activity of CaN in myocardial tissue of the middle-. high dose groups of Yi-Xin tai and Losartan Potassium group were significantly lower (P<0.05or P<0.01);(5)compared with the model group, the protein expression of NFAT3> P-NFAT3、GATA4and C-Myc in myocardial tissue of the treatment groups were significantly lower (P<0.05or P<0.01); compared with the low dose group, the protein expression of NFAT3-. GATA4and C-Myc in myocardial tissue of the middle, high dose groups of Yi-Xin tai and Losartan Potassium group were significantly lower (P <0.05or P<0.01);(6)compared with the model group, the expression of NFAT3mRNA. GATA4mRNA, C-Myc mRNA of the middle, high dose groups of Yi-Xin tai and Losartan Potassium group were significantly lower (P<0.01); compared with the low dose group, the expression of NFAT3mRNA. GATA4mRNA. C-Myc mRNA of the middle, high dose groups of Yi-Xin tai and Losartan Potassium group were significantly lower (P<0.05or P<0.01)o(7) Compared with the model group, the damage of the myocardial cell of the treatment groups were alleviated; the infiltration of inflammatory cell reducted and ademo lightened.The myocardial ultrastructure was also significantly improved compared with the model group.Conclusion Yi-Xin tai can inhibit the myocardial remodeling and improve the cardiac function of the rabbit with chronic heart failure through inhibiting the Ca2+-CaN-NFAT3signal pathway.And the curative effect of medial and high dose groups of Yi-Xin tai is better than the low dose group.更多还原