比索洛尔对慢性心力衰竭大鼠心肌纤维化及ERK信号通路的影响

Effects of bisoprolol on myocardial fibrosis and ERK signaling pathway in chronic heart failure rats

目的观察比索洛尔对慢性心力衰竭(CHF)大鼠心肌纤维化及心肌组织细胞外调节蛋白激酶(ERK)信号通路的影响。方法将115只大鼠随机分为3组,每组35只。模型组和治疗组均腹腔注射阿霉素建立CHF大鼠模型,对照组腹腔注射等量生理盐水。建模成功后,治疗组给予比索洛尔灌胃,模型组、对照组均给予等量蒸馏水灌胃,连续灌胃35 d;同时,模型组和治疗组继续每周腹腔注射阿霉素1次。治疗前后,应用彩超检查大鼠心脏功能[左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD)、左心室后壁厚度(LVPWD)、左心室短缩分数(FS)、心输出量(CO)、左心室射血分数(LVEF)],测量心室重构指标左心室质量指数(LVMI)、右心室质量指数(RVMI),HE染色观察大鼠心室肌组织病理学变化,计算心肌纤维化指标心肌胶原容积分数(CVF),用Western blotting法检测心肌组织中的ERK、p-ERK及促心肌纤维化细胞因子转化生长因子β1(TGF-β1)。结果与对照组比较,模型组FS、CO、LVEF均降低,LVEDD、LVESD、LVPWD、LVMI均升高(P均<0.05);与模型组比较,治疗组FS、CO、LVEF均升高而LVMI降低(P均<0.05)。模型组心肌细胞较对照组出现排列紊乱、细胞肥大增粗、细胞间质增加及炎性细胞浸润等,而治疗组心肌细胞上述变化均明显减轻。治疗组、模型组ERK、p-ERK、TGF-β1蛋白表达均较对照组升高,治疗组p-ERK、TGF-β1蛋白表达均较模型组降低(P均<0.05)。结论比索洛尔可抑制CHF大鼠心肌组织纤维化,减轻心室肥厚,延缓心肌间质重构,从而提高心脏功能;这可能与其抑制EFR蛋白磷酸化信号转导通路,降低TGF-β1表达水平有关。

Objective To observe the effects of bisoprolol on myocardial fibrosis and extracellular regulated protein kinase （ERK） signaling pathway of myocardial tissues in chronic heart failure （CHF） rats. Methods Totally 115 rats were randomly divided into three groups, with 35 in each group. The rats in the model group and the treatment group were injected intraperitoneally with doxorubicin to establish the CHF rat models, and the rats in the control group were injected intraperitoneally with the same amount of saline. After the successful modeling, the treatment group was given bisoprolol intragastrically, the model group and control groups were given the equal volume of distilled water. The rats were continuously given by intragastric administration for 35 days. At the same time, the rats in the model group and the treatment group continued to receive intraperitoneal injection of doxorubicin once a week. Before and after treatment, the heart function was examined by color doppler ultrasonography [left ventricular end-diastolic dimension （LVEDD）, left ventricular end systolic dimension （LVESD）, left ventricular posterior wall depth （LVPWD）, left ventricular systolic fraction （FS）, cardiac output （CO）, and left ventricular ejection fraction （LVEF）]. The left ventricular mass index （LVMI） and right ventricular mass index （RVMI） were measured. HE staining was used to observe the histopathological changes of ventricular myocardium in rats and the myocardial fibrosis index cardiac collagen volume fraction （CVF） was calculated. ERK, p-ERK, and myocardial fibrosis cytokines transforming growth factor-β 1 （TGF-β 1） were detected by Western blotting.Results Compared with the control group, the FS, CO, and LVEF in the model group decreased and the LVEDD, LVESD, LVPWD and LVMI increased in the model group （all P 〈0.05）. Compared with the model group, the FS, CO, and LVEF increased and the LVMI decreased in the treatment group （all P 〈0.05）. Compared with the control group, the myocardial cells were in disordered arrangement, and enlarged and thickened cells, increased intercellular matrix and inflammatory cell infiltration were found in the model group, while the above changes of the myocardial cells in the treatment group were significantly reduced. The expression levels of ERK, p-ERK, and TGF-β 1 in the treatment and model groups were all higher than those in the control group. The expression levels of p-ERK and TGF-β 1 in the treatment group were lower than those in the model group （both P 〈0.05）.Conclusion Bisoprolol can inhibit the myocardial fibrosis, reduce ventricular hypertrophy, and delay myocardial remodeling in CHF rats, and thus improve cardiac function by inhibiting the EFR protein phosphorylation signal transduction pathway and decreasing the expression of TGF-β 1.