海南医科大学学报

目的：基于STAT3信号通路研究益气活血开心汤对心肌梗死合并抑郁症大鼠模型大鼠心肌及海马的影响。方法：将SD大鼠随机分为对照组、模型组、益气活血开心汤低剂量（8.24 g/kg）组、益气活血开心汤高剂量（32.97 g/kg）组、西药（酒石酸美托洛尔20 mg/kg、盐酸氟西汀胶囊3.1 mg/kg）组，每组8只。除对照组外，其他各组采用采用结扎冠状动脉左前降支结合慢性不可预见性轻度应激方法制备大鼠心肌梗死合并抑郁模型，再按剂量各组灌胃给药。灌胃28 d后观察大鼠抑郁行为，观察各组大鼠心脏和海马组织病理变化，采用Western blot检测心脏和海马STAT3、p-STAT3蛋白表达，免疫荧光检测p-STAT3大鼠心脏和海马定位表达情况，ELISA检测大鼠血清中CK-MB、cTnT、IL-17、IL-10的水平。结果：行为学结果显示：与对照组相比，模型组大鼠水平得分和垂直得分显著减少（P<0.01），糖水消耗量明显降低（P<0.01）；与模型组相比，益气活血开心汤低、高剂量组及西药组水平得分和垂直得分均有不同程度增加（P<0.05），糖水偏好率均有不同程度升高（P<0.01）。病理染色结果显示：与对照组相比，模型组大鼠心肌细胞大量坏死，排列紊乱，可见大量胶原纤维、粘液沉积，海马神经细胞坏死明显，细胞数量少，核固缩，排列松散；与模型组相比，益气活血开心汤低、高剂量组及西药组心肌病理结构均有所改善，炎性浸润减少，纤维化情况得到明显改善，海马神经细胞数量相对较多，层次丰富，形态相对规则。ELISA和Western blot结果显示：与对照组相比，模型组大鼠血清IL-17、CK-MB和cTnT显著升高（P<0.01）,IL-10显著下降（P<0.01），心脏和海马p-STAT3/STAT3蛋白表达量均显著升高（P<0.01）；与模型组相比，益气活血开心汤低、高剂量组及西药组IL-17、CK-MB和cTnT显著下降（P<0.01）,IL-10显著升高（P<0.01），心脏和海马p-STAT3/STAT3蛋白表达量均显著下降（P<0.01）。免疫荧光结果显示：与对照组相比，模型组大鼠定位于心脏和海马的pSTAT3蛋白荧光强度显著增强；与模型组相比，益气活血开心汤低、高剂量组及西药组定位于心脏和海马的p-STAT3蛋白荧光强度显著减弱。结论：益气活血开心汤可能通过抑制STAT3介导的炎症因子的表达而改善心肌纤维化情况和海马神经元的损伤治疗心肌梗死合并抑郁模型大鼠。

Objective: To study the effects of Yiqi Huoxue Kaixin Decoction on myocardial muscle and hippocampus of rats with myocardial infarction complicated with depression based on STAT3 signaling pathway. Methods: SD rats were randomly divided into the control group, the model group, the Yiqi Yiqi Huoxue Kaixin Decoction low-dose(8.24 g/kg) group, the Yiqi Huoxue Kaixin Decoction high-dose(32.97 g/kg) group, and the western medicine(metoprool tartrate 20 mg/kg and fluoxetine hydrochloride capsule 3.1 mg/kg) group, with 8 rats in each group. Except for the control group, the rat model of myocardial infarction complicated with depression was prepared by ligation of the left anterior descending coronary artery combined with chronic unforeseeable mild stress. After 28 d of intragastric administration, depression behavior and pathological changes of the heart and hippocampus were observed. Western blot was used to detect the expression of STAT3 and p-STAT3 protein in the heart and hippocampus, and immunofluorescence was used to detect the locational expression of p-STAT3 in the heart and hippocampus. The serum levels of CK-MB, cTnT, IL-17, and IL-10 were detected by ELISA. Results: The behavioral test results showed that compared to the control group, the horizontal scores and vertical scores of rats in the model group were significantly decreased(P<0.01), and the consumption of sugar water was significantly decreased(P<0.01). Compared to the model group, the horizontal scores and vertical scores of the low-and high-dose Yiqi Huoxue Kaixin Decoction groups and the western medicine group were increased in different degrees(P<0.05), and the sugar water preference rate was increased in different degrees(P<0.01). The pathological staining results showed that, compared to the control group, the myocardial cells in the model group were necrotic and disordered, with a large amount of collagen fibers and mucus deposition, hippocampal nerve cells were necrotic, the number of cells was small, the nuclei shrank, and the arrangement was loose. Compared to the model group, the myocardial pathological structure of the low-and high-dose Yiqi Huoxue Kaixin Decoction groups and western medicine group were improved, the inflammatory infiltration was reduced, the fibrosis was significantly improved, the number of hippocampal nerve cells was relatively large, the layers were rich, and the shape was relatively regular. ELISA and Western blot results showed that compared to the control group, serum IL-17, CK-MB, and cTnT in the model group were significantly increased(P<0.01), IL-10 was significantly decreased(P<0.01), and p-STAT3/STAT3 protein expression levels in the heart and hippocampus were significantly increased(P<0.01). Compared to the model group, IL-17, CK-MB, and cTnT were significantly decreased(P<0.01), IL-10 was significantly increased(P<0.01), and p-STAT3/STAT3 protein expression levels in the heart and hippocampus were significantly decreased(P<0.01) in the low-and high-dose Yiqi Huoxue Kaixin Decoction groups and the western medicine group. The results of immunofluorescence showed that compared to the control group, the fluorescence intensity of p-STAT3 protein in the heart and hippocampus of the model group was significantly enhanced. Compared to the model group, the fluorescence intensity of pSTAT3 protein in the heart and hippocampus of the low-and high-dose Yiqi Huoxue Kaixin Decoction groups and western medicine group was significantly decreased. Conclusion: Yiqi Huoxue Kaixin Decoction may improve myocardial fibrosis and the damage of hippocampal neurons by inhibiting the expression of STAT3-mediated inflammatory factors in myocardial infarction complicated with depression.