缬沙坦对脓毒症大鼠心肌细胞凋亡的影响

EFFECT OF VALSARTAN ON CARDIOMYOCYTE APOPTOSIS IN RATS WITH SEPSIS

目的探讨缬沙坦对脓毒症大鼠心肌细胞凋亡的影响及其作用机制。方法雄性SD大鼠50只,按照随机数字表法分为对照组(A组)、假手术组(B组)、脓毒症组(C组)、小剂量缬沙坦组(D组)、大剂量缬沙坦组(E组)5组,C、D、E组采用盲肠结扎穿孔法复制脓毒症大鼠模型,观察各组大鼠的行为学变化、生存情况及腹部体征的变化。术后24h再次麻醉后分离左心室,一部分心肌组织行石蜡包埋、HE染色和原位末端脱氧核苷酸转移酶标记染色,观察缬沙坦对心肌的显微结构和凋亡情况的影响;其余心肌组织采用酶联免疫吸附法测定凋亡蛋白B细胞淋巴瘤因子2(Bcl-2)、半胱氨酸蛋白酶3(Caspase-3)、P53蛋白的表达变化。结果与A、B组比较,C组凋亡指数、Caspase-3、P53蛋白的表达明显升高,病理损伤明显加重,Bcl-2的表达明显下降(P<0.05);而D组与C组比较Caspase-3和P53蛋白含量差异无显著性(P>0.05);E组凋亡指数、Caspase-3、P53蛋白的表达均较C组明显降低(P<0.05),Bcl-2的表达明显升高(P<0.05),病理损伤明显减轻。结论大剂量缬沙坦通过抑制外源性、内源性凋亡途径,减少Caspase-3的表达而发挥抑制细胞凋亡、减轻心肌病理损伤的作用,但小剂量缬沙坦的抑制作用并不显著。

Objective To investigate the effect of valsartan on cardiomyocyte apoptosis in rats with sepsis and its possible mechanism of action. Methods A total of 50 male Sprague-Dawley rats were divided into control group （group A）, sham-ope-ration group （group B）, sepsis group （group C）, low-dose valsartan group （group D）, and high-dose valsartan group （group E） using a random number table, with 10 rats in each group. Cecal ligation and puncture was used to establish a rat model of sepsis in groups C, D, and E, and the behavioral changes, survival, and the changes in abdominal signs were observed for all groups. At 24 h after surgery, anesthesia was performed again and the left ventricule was separated. Paraffin embedding, HE staining, and TdT-mediated dUTP-biotin nick end labeling （TUNEL） staining were performed for a part of myocardial tissue samples to observe the effect of valsartan on myocardial microstructure and cardiomyocyte apoptosis. ELISA was performed for the rest of the myocardial tissue samples to measure the changes in the expression of Bcl-2, caspase-3, and P53. Results Compared with groups A and B, group C had significant increases in apoptotic index and the expression of caspase-3 and P53, significantly greater pathological injuries, and a significant reduction in the expression of Bcl-2 （ P 〈0.05）. There were no significant differences in the levels of caspase-3 and P53 between groups D and E （ P 〉0.05）. Compared with group C, group E had significant reductions in apoptotic index and the expression of caspase-3 and P53 （ P 〈0.05）, a significant increase in the expression of Bcl-2 （ P 〈0.05）, and significantly alleviated pathological injuries. Conclusion Valsartan can inhibit cardiomyocyte apoptosis and alleviate pathological injuries of the myocardium by inhibiting the exogenous and endogenous apoptotic pathways and reducing the expression of caspase-3, but low-dose valsartan does not have a marked inhibitory effect.