摘要
目的探讨慢性心衰兔心肌核因子-κB（NF-κB）活化与心肌凋亡的关系以及N-乙酰半胱氨酸（NAC）的作用机制。方法健康日本大耳白兔共50只，雌雄不限（武汉大学医学院实验动物中心提供），随机选取10只设为对照组。余40只兔采用盐酸阿霉素复制心衰模型（阿霉素1mg／kg，每周2次，连续8周），造模成功25只，随机分为心衰组（n=12）和NAC干预组（n=13），NAC组给予NAC注射液（300mg／kg）耳缘静脉注射，每天1次共4周。对照组与心衰组均注射等体积生理盐水。观测血流动力学指标、心肌凋亡指数、血清和心肌总抗氧化能力、bcl-2、Bax蛋白在心肌细胞中表达的水平，以及Nn-cBp65的表达和核结合活性的改变。通过t检验、方差分析和直线相关分析等统计学方法，观察NAC对上述指标的影响。结果对照组、心衰组和NAC组心肌细胞凋亡指数（AI）分别为1．57％、55．62％和21．71％，NAC组较心衰组心肌细胞凋亡率显著降低（P〈0．001）。心衰组Bax蛋白、NF-κBp65的核内表达增高，bcl-2表达下调，bcl-2／Bax比值和总抗氧化能力[血清中（8．86±2．21）U／ml，心肌中（1．26±0．30）U／mgprot]下降。NAC可不同程度地改善心功能指标，降低心肌凋亡指数和Bax的表达，显著降低NF-κBp65核内表达及升高总抗氧化能力[血清中（13．23±2．92）U／ml，心肌中（1．58±0．19）U／mgprot]、bcl-2／Bax比值和bcl-2的表达。结论氧化应激可激活NF-κB，启动bcl-2和Bax的转录调节相应蛋白的合成，介导心肌凋亡，促进慢性心衰的发生发展。NAC具有抗氧化作用，通过降低心肌NF-κB活性，减少心肌细胞凋亡，改善心功能。
Objective To investigate the relationship between activation of nuclear factor-roB （NF-κB） and the progression cardiomyocyte apoptesis, and the mechanisms of N-acetylcysteine （NAC） in therapies for chronic heart failure （HF） in rabbits. Method There were 50 adult Japanese white rabbits, male or female, provided by experimental animal center of Wuhan University College of Medicine. Ten rabbits were randomly selected and served as control group, the other rabbits were modelled by intravenous injection of adriamycin at a dose of 1 nag/ kg twice a week for 8 weeks to induce heart failure. Totally 25 rabbits were successful, and were randomly divided into heart failure group （ n = 12） and NAC group （ n = 13）. N-acetylcysteine was administered intravenously to rabbits in dose at 300 mg/kg daily for 4 weeks. The control group and heart failure group received the same doses of 0.9 % sodium chloride simultaneously. After 4 weeks, hemodynamics, the index of cardiomyocyte apoptosis, the level of total antioxiclation capacity （TAOC） in serum or myocardium, expression of bel-2 and Bax protein, and the nuclear binding activity of NF-κB were measured in three groups. Effects of NAC on above index throught the means of statistics were examined. Results The apaptosis index of cardiomyocyte was 1.57%, 55.62% and 21.71 % in control group, heart failure group and NAC group, respectively. Cardiomyocyte apaptasis rate in NAC group was much lower than that in heart failure group （ P 〈 0.001 ）. In the HF group, expression of Bax protein and activity of NF-κB were significantly higher and the expression of bcl-2 protein, the ratio of bcl-2/Bax and the level of TAOC （8.86± 2.21 U/ml in serum, 1.26±0.30 U/mgprot in myocardium） were lower than those of control group. NAC improved hemodyanmic parameters in rabbits with heart failure, decreased the apoptosis index, expression of Bax protein and activity of NF-κB, and increased the myocardial levels of TAOC （ 13.23 ± 2.92 U/ml in serum, 1.58± 0.19 U/mgprot in myocardium）. The ratio of bcl-2/Bax and expression of bcl-2 protein in NAC group were higher than those in HF group. Conclusions NF-κB activated by oxidative stress in cardiomyocyte initiates bcl-2 and Bax gene transcription and protein synthesis respectively, induces cardiacmyocyte apoptosis and promotes the onset and progression of chronic HF after ADR injection. NAC can effectively ameliorate heart ftmtcion, decrease myocardium apoptosis by antioxidation and inhibiting activation of NF-κB.
出处
《中华急诊医学杂志》
CAS
CSCD
2008年第3期276-280,共5页
Chinese Journal of Emergency Medicine
