N-乙酰半胱氨酸对阿霉素致心力衰竭兔心肌细胞凋亡的作用

N-acetylcysteine acts on cardiomyocyte apoptosis in heart failure rabbits induced by adriamycin

目的:探讨慢性心力衰竭(HF)兔心肌核因子-κB(NF-κB)活化、诱生型一氧化氮合酶(iNOS)与心肌细胞凋亡的关系以及N-乙酰半胱氨酸(NAC)对心肌细胞凋亡的作用。方法:设立对照组,剩余动物以阿霉素复制HF模型,随机分为HF组和NAC组,药物干预4周。观测3组心肌细胞凋亡指数、血清和心肌一氧化氮(NO)浓度、iNOS蛋白在心肌细胞中表达的水平,以及NF-κB p65的核表达和结合活性的改变,观察NAC对上述指标的影响。结果:与对照组比较,HF组心肌细胞凋亡指数增高,iNOS蛋白表达增多,NF-κB p65易位和核内表达增多,血清和心肌NO浓度升高(P<0.001),NF-κB p65活化与iNOS表达呈直线相关(r=0.973,P<0.001)。NAC组结果示NAC可显著减少NF-κB p65核内表达及iNOS蛋白的表达,降低血清和心肌NO水平,降低心肌细胞凋亡指数(P<0.01～0.001)。结论:HF时心肌细胞中NF-κB的活化及其促进iNOS的转录合成导致NO大量生成,参与了心肌凋亡的发生。NAC可显著拮抗NF-κB的大量活化核表达,减弱iNOS的表达上调,抑制NO的生成,减少心肌细胞凋亡。NF-κB的活化可能是iNOS表达的重要调控机制之一。

Objective：To explore the connection between the activation of nuclear factor-κB（NF-κB）,the expression of inducible nitric oxide synthase（iNOS） and the progression of cardiomyocyte apoptosis,and how N-acetylcysteine（NAC） impact on cardiomyocyte apoptosis.Method：An animal model of heart failure was induced by adriamycin（ADR） in rabbits.The animals were randomly assigned into two groups： heart failure group（HF group） and N-acetylcysteine group（NAC group）.Meanwhile,normal rabbits were established as a control group.After 4 weeks of remedy,the index of cardiomyocyte apoptosis,the concentration of nitric oxide in serum or myocardium,the expression of iNOS protein,and the nuclear binding activity of NF-κB were investigated in 3 groups.Result：In the HF group,the apoptosis index,the level of nitric oxide,expression of iNOS protein and activity of NF-κB were significantly higher than those of the control group（all P0.001）.Furthermore,a linear correlation was observed between NF-κB activation and iNOS expression（r=0.973,P0.001）.The results of NAC group indicated that NAC markedly decreased these indexes（P0.001 for the activity of NF-κB,the expression of iNOS protein,the level of nitric oxide in serum and the apoptosis index in rabbits with heart failure;P0.01 for the level of nitric oxide in myocardium）.Conclusion：iNOS gene transcription and protein synthesis activated by NF-κB in cardiomyocyte produce a lot of nitric oxide,which induces cardiacmyocyte apoptosis and promotes the onset and progression of chronic heart failure after adriamycin injection.NAC can effectively attenuate expression of iNOS protein,inhibit the production of nitric oxide and decrease myocardium apoptosis by antioxidation and antagonizing activation of NF-κB.The activation of NF-κB may represent an important regulatory factor for the expression of iNOS in rabbits with heart failure.