辛伐他汀对慢性心力衰竭幼兔心肌嗜铬粒蛋白A、细胞凋亡信号调节激酶1表达的影响

Effect of Simvastatin on expressions of myocardial chromogranin A and apoptosis signal - regulating kinase 1 of immature rabbits with chronic heart failure

目的观察辛伐他汀干预慢性心力衰竭幼兔模型的疗效，探讨辛伐他汀防治心力衰竭的可能机制。方法将30只雄性幼兔按随机数字表分为3组：对照组（CON组）、心力衰竭组（HF组）、辛伐他汀组（SIM组），每组各10只。慢性心力衰竭模型采用多次注射多柔比星的方法建立（1.5 mg/kg，每周1次，共12周），CON组则用9 g/L盐水代替，SIM组在注射多柔比星的同时予1.5 mg/kg辛伐他汀灌胃，每日1次，共12周。造模结束后观察幼兔心功能、心肌形态学改变及心肌嗜铬粒蛋白A（CgA）、细胞凋亡信号调节激酶1（ASK1）的表达。结果1.CON组幼兔全部存活，饮食、活动等均正常；SIM组与HF组幼兔均出现不同程度的饮食减少、行动缓慢、精神不振等症状。HF组幼兔存活率为60%，SIM组幼兔存活率为80%。2.心脏超声结果：与CON组比较，HF组、SIM组幼兔的左心室射血分数均下降[（40.05±6.74）%、（50.18±5.73）%比（65.93±5.65）%，均P〈0.01]，其中SIM组高于HF组，差异有统计学意义（P〈0.05）；SIM组左心室舒张末期内径、左心室收缩末期内径较HF组减小[（13.48±1.24） mm比（16.23±2.82） mm；（9.87±0.85） mm比（11.13±1.21）mm]，差异均有统计学意义（均P〈0.05）。3.免疫组织化学结果：与CON组相比，HF组、SIM组幼兔心肌中CgA（平均光密度值142.24±17.14、127.93±12.12比78.65±6.78，P〈0.05；累计光密度值1 422.41±167.34、1 279.37±118.15比786.54±75.84，P〈0.05）、ASK1（平均光密度值140.32±18.65、115.48±12.30比69.85±6.54，P〈0.05；累计光密度值1 403.23±165.67、1 158.79±137.81比698.58±64.51，P〈0.05）表达均显著增加，其中SIM组表达少于HF组，差异有统计学意义（P〈0.05）。结论辛伐他汀对慢性心力衰竭幼兔可发挥心肌保护作用，其机制可能与抑制心肌CgA、ASK1的表达有关。

Objective To observe the influence of Simvastatin on immature rabbit model of chronic heart failure（CHF） ,and to explore the possible protective mechanism of Simvastatin for the rabbits with CHF. Methods Thirty immature male rabbits were divided into 3 groups randomly： control group, heart failure group （HF group）and Simvastatin group（ SIM group） , 10 rabbits in each group. The models of CHF were established by injecting Adrinmycin via the auricular vein of rabbits （1.5 mg/kg, once 1 week,for 12 weeks）. The control group were injected the same amount of 9 g/L saline. SIM group were given both injection of Adrinmycin and Simvastatin[ 1.5 mg/（ kg · d） for 12 weeks]. The immature rabbit＇s cardiac function and myocardial morphology changes were evaluated. The expressions of chromogranin A （CgA） and apoptosis signal - regulating kinase 1 （ ASK1 ） were evaluated. Results （ 1 ） In control group, the immature rabbits were all alive;in the other 2 groups, most immature rabbits were depressed and sluggish. The survival rate of HF group was 60% , while in SIM group the survival rate was 80%. （2）Compared with the control group, the left ventricular ejection fraction in HF group and SIM group decreased significantly [ （ 40.05 ± 6.74 ） %, （ 50.18 ± 5.73 ） % vs. （ 65.93 ± 5.65 ） % , all P 〈 0. 01 ], while in SIM group was higher than that of HF group, and the difference was significant （ P 〈 0.05 ） ; compared with HF group, the left ventricular end diastolic diameter and left ventricular end systolic diameter decreased in SIM group [ （ 13.48 ± 1.24 ） mm vs. （ 16.23 ± 2. 82 ） mm; （ 9.87 ± 0.85 ） mm vs. （ 11.13 ± 1.21 ）mm ] , and the differences were significant （ all P 〈 0.05 ）. （3） Compared with the control group, the expression of CgA（ mean optical density 142.24 ± 17. 14,127.93 ± 12.12 vs. 78.65 ± 6.78, P 〈 0.05 ; integrated optical density 1 422.41 ± 167.34, 1 279.37 ± 118.15 vs. 786.54 ± 75.84, P 〈 0. 05 ） and ASK1 （ mean optical density 140.32 ± 18. 65,115.48 ± 12.30 vs. 69.85 ± 6.54, P 〈 0.05 ; integrated optical density 1 403.23 ± 165.67,1 158.79 ± 137.81 vs. 698.58 ± 64.51, P 〈 0.05 ） increased in the HF group and SIM group. While the expression in the SIM group decreased significantly compared with that of the HF group, and the difference was significant （ P 〈 0. 05）. Conclusions Simvastatin can improve cardiac function of immature rabbits with CHF. The mechanism of SIM may depress the expressions of CgA and ASK1.