Neuregulin对快速起搏所致猴心力衰竭心肌细胞凋亡及磷脂酰肌醇3激酶信号转导途径的影响

Effects of neuregulin on cardiac myocyte apoptosis and PI-3K signal transduction pathway in rapid pacing-induced heart failure in rhesus monkeys

目的:探讨Neuregulin(NRG)对快速起搏所致猴心力衰竭心肌细胞损伤的保护作用及其可能的机制。方法:采用颈总动脉插管技术,测定左心室的最大压力上升速度(LVdp/dtmax)、左心室舒张末期压(LVEDP)、左心室收缩末期压(LVSP)等血流动力学指标改变;采用电化学发光法测定脑钠肽(BNP)含量;通过TUNEL法检测心肌细胞凋亡指数;通过Western印迹法检测凋亡相关基因Bcl-xl蛋白水平及磷酸化蛋白激酶B蛋白水平(Phospho-PKB)。结果:起搏状态下连续10d静脉注射给予3μg/kg重组人NRG后,左心室的最大压力上升速度(LVdp/dtmax)显著升高,脑钠肽水平降低;快速起搏诱导的心肌细胞凋亡受到明显抑制;同时心肌组织蛋白激酶B活性显著增强,Bcl-xl蛋白水平也明显增加。结论:NRG保护快速起搏所致猴心力衰竭心肌细胞损伤,其机制可能是通过调节PI-3K信号转导通路来对抗心肌细胞凋亡。

Objective To explore the protective effect of neuregulin against cardiac myocyte injury in pacing-induced heart failure in rhesus monkeys and its mechanism. Methods Rapid pacing was used to induce heart failure in rhesus monkeys. Aorta intubation was used to perform hemodynamic measurements such as the peak positive rate of of left ventricular pressure （ LVdP/dtmax ） and left ventricular systolic, end-diastolic blood pressures （LVSP and LVEDP, respectively ） 17 days after the pacing. N-terminal pro-brain natriuretic peptide （ BNP ） , as molecular marker of heart failure, was also measured by electrochemical luminescence immunoassay. The apoptosis of cardiac myocyte was observed by Tunel method. Western blot was used to detect the PKB activity and the relative amounts of Bcl-xl protein in the left ventricular free walls. Results After the daily intravenous injection of 3 μg/kg recombinated neuregulin for 10 days, LVdP/dtmax increased significantly while BNP decreased remarkably. The apoptotic index was obviously lower, and Bcl-xl and activity of PKB were higher. Conclusion Neuregulin protects against rapid pacing-induced apoptosis in heart failure in rhesus monkeys and the mechanism might be attributed to the increase of the activity of PKB and Bcl-xl protein.