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目的探讨重组人血管内皮抑素(rh-ES)对大鼠心肌的毒性作用及其可能机制。方法 24只成年雌性Wistar大鼠随机分为rh-ES低、中、高剂量组[分别予3、6、12mg/(kg·d)rh-ES腹腔注射]及对照组(腹腔注射等体积生理盐水),每组6只。各组在第4周和第8周末次给药后采用脊椎脱臼法分别处死3只大鼠,在光镜及电镜下观察病理形态学及超微结构改变,TUNEL法检测大鼠心肌细胞凋亡情况,CD34标记内皮细胞免疫组化法检测大鼠心肌组织的微血管密度(MVD)改变。结果光镜及电镜下对照组和低、中剂量组无明显心肌损伤的病理形态及超微结构改变。高剂量组光镜下可见心肌损伤的病理形态及超微结构改变。TUNEL法检测显示,给药8周后中剂量组和高剂量组凋亡指数明显高于对照组,差异有统计学意义(P=0.033、P=0.000),其中高剂量组凋亡指数最高。心肌组织微血管计数提示,给药4周及8周后高剂量组(MVD)增加,显著高于对照组(P<0.05)。结论 rh-ES对大鼠心肌细胞具有毒性作用,细胞凋亡机制参与了心肌损伤的病理过程。
Objective To investigate the toxic effect of recombinant human endostatin (rh-ES) on myocardium of rats and its possible mechanism. Methods Twenty-four adult female Wistar rats were randomly divided into rh-ES low, middle and high dose groups (intraperitoneal injection of 3,6,12 mg / (kg · d) rh-ES) and control group Saline), 6 in each group. The rats in each group were sacrificed at the end of the fourth week and the end of the eighth week, respectively. Three rats were killed by the method of dislocation of the spine. The pathological changes and ultrastructure were observed under light microscope and electron microscope. The apoptosis of rat myocardial cells was detected by TUNEL method. The changes of microvessel density (MVD) in rat myocardium were detected by CD34 labeled endothelial cell immunohistochemistry. Results The histopathological changes and ultrastructural changes of myocardial injury in the control group and the low and middle dose groups under light and electron microscopes were not significant. The pathological changes and ultrastructural changes of myocardial injury in high dose group were observed under light microscope. TUNEL assay showed that the apoptotic index of middle dose group and high dose group was significantly higher than that of control group after 8 weeks of treatment (P = 0.033, P = 0.000), and the apoptosis index of high dose group was the highest. Myocardial microvessel count suggested that the high-dose group (MVD) increased at 4 weeks and 8 weeks after administration, which was significantly higher than that of the control group (P <0.05). Conclusion rh-ES has a toxic effect on rat cardiomyocytes, and the apoptosis mechanism is involved in the pathological process of myocardial injury.