曲妥珠单抗诱导大鼠心功能降低及其机制的探讨

Research on cardiac dysfunction induced by trastuzumab and the possible mechanisms

目的观察曲妥珠单克隆抗体对大鼠心功能的影响,并初步探讨其可能的作用机制。方法雄性Wistar大鼠20只,随机分成实验组(n=10)和对照组(n=10)。实验组第1天腹腔注射曲妥珠(12 mg/kg),此后6 mg/(kg·d),连续6 d,累计总量48 mg/kg;对照组注射相应体积的生理盐水。给药前后分别进行心脏超声检测,观察心功能变化。运用TUNEL法检测细胞凋亡并计算凋亡指数;分光光度法检测Caspase-3活性。结果与对照组相比,实验组大鼠左室内径(LVED)扩大,左室后壁(LVPW)变薄,左室射血分数(LVEF)降低,左室短轴缩短率(LVFS)下降(P均<0.01);实验组大鼠心肌细胞凋亡计数和Caspase-3活性均显著升高(P均<0.001)。Caspase-3活性与室壁厚度(r=0.832)和左室射血分数(r=0.756)均呈负相关(P均<0.05)。结论连续多次腹腔注射曲妥珠单抗可损害大鼠心脏功能,其机制可能与心肌细胞凋亡增加有关。

Objective To observe the effect of trastuzumab on cardiac function of rats and to investigate the possible mechanisms. Methods A total of 20 Wistar rats were randomly divided into the experimental and control group, with 10 in each. Rats in the experimental group received dally intraperitoneal injection of trastuzumab （ 12 mg/kg in the first day and then 6 mg/kg in the following 6 days）. The cumulative dose of trastuzumab was 48 mg/kg. Rats in the control group were given the same volume of saline. The cardiac function was evaluated with echocardiogram before and after trastuzumab administration. Myocardial cell apoptosis was determined with terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） staining. Apoptotic index was calculated with reference to the results of TUNEL staining. The activity of Caspsase-3 was measured with colorimetic assay. Results Compared with the control group, in the experimental group, the left ventricular end systolic diameter （LVED） significantly increased; the left ventricle posterior wall （LVPW） became thinner; the left ventricular ejection fraction （LVEF） reduced; the left ventricular fractional short- ening （LVFS） declined（P 〈 0.01 ） ; the number of apoptotic myocardial cells and activity of Caspase-3 were both signifi- cantly higher （ P 〈 0.001 ）. The degree of myocardial cell apoptosis was positively associated with left ventricular diameter and negatively correlated with left ventricular wall thickness. Conclusion Consecutive multiple intraperitoneal injections of trastuzumab could impair cardiac function in rats, which may be associated with the apoptosis of myocardial cells.