自噬基因Beclin-1和微管相关蛋白LC3在大鼠阿霉素心肌病中的表达及其意义的实验研究
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摘要
目的:探讨自噬基因Beclin-1及微管相关蛋白LC3在大鼠阿霉素(Adriamycin,ADR)心肌病中的表达及其意义,初步证实自体吞噬(Autophagy)参与了大鼠阿霉素心肌病的发病,并探讨其机制,为临床阿霉素心肌病的防治提供理论依据。
方法:雄性(Sprague-Dawley)SD大鼠45只,体重在180～200克之间,随机分为3组,阿霉素(ADR)组(N=15),阿霉素(ADR)+3-甲基腺嘌呤(3-Methyladenine,3-MA)组(N=15),对照组(N=15)。阿霉素(ADR)组:实验的第二天起腹腔注射阿霉素4mg/kg,每周一次,共6周,累计剂量24mg/kg;阿霉素(ADR)+3-甲基腺嘌呤(3-MA)组:实验的第二天起腹腔注射同等剂量的阿霉素,在注射前半小时腹腔注射自噬抑制剂3-甲基腺嘌呤(3-MA)500nmol(5ul);对照组:腹腔注射等量的生理盐水。实验第六周末大鼠称重并心脏彩超测量左室收缩功能(射血分数EF及缩短分数FS),心脏取血分光光度法检测血浆中丙二醛(malondialdehyde,MDA)及全血中还原型谷胱甘肽(reduced glutathione,GSH)含量,取心脏并称重后计算心脏重量指数(heart weight index,HWI),取左心室心肌标本,HE(hematoxylin and eosin)染色观察心肌病理改变,电镜观察自噬体形态及数量,免疫印迹法(west-blotting)检测心肌组织中自噬基因Beclin-1的含量,免疫组化S-P法测定心肌细胞微管相关蛋白(Microtubule-associate Protein 1Light Chain 3,LC3)含量。所有数据均采用SPSS11.5统计软件进行统计分析。
结果:1、ADR组大鼠左室收缩功能较对照组下降,P＜0.05,具统计学意义;ADR组大鼠心脏重量指数(HWI)较对照组增高,P＜0.05,具统计学意义;
2、ADR组血浆MDA含量较对照组增高,P＜0.05,具统计学意义,ADR组全血GSH含量较对照组减低,P＜0.05,具统计学意义;
3、免疫印迹法显示:ADR组心肌组织中Beclin-1水平较对照组及ADR+3-MA组增高,P＜0.05,具统计学意义;
4、免疫组织化学染色显示:ADR组心肌组织中LC3含量较对照组及ADR+3-MA组增高,P＜0.05,具统计学意义;
5、直线相关分析:自噬基因Beclin-1水平与微管相关蛋白LC3含量呈显著正相关。
结论:1、阿霉素可引起大鼠心肌组织中自噬基因Beclin-1水平上调,从而诱导心肌自噬性程序性细胞死亡,导致心肌病变的发生。
2、阿霉素心肌病大鼠心肌细胞中微管相关蛋白LC3含量明显增高,且与自噬基因Beclin-1水平呈显著正相关。
3、自噬性程序性细胞死亡(Autophagy)作为除坏死及调亡以外的另一种程序性细胞死亡方式(programmed cell death,PCD)参与了阿霉素心肌病的发病,并可被自噬抑制剂3-MA抑制。
Objective:To explore the expression and significance of autophagy-related gene Beclin-1 and Microtubule-associated Protein 1 Light Chain 3(LC3) in Adriamycin Induced Cardiomyopathy in rats,prove that Autophagy take part in the development of Adriamycin Induced Cardiomyopathy in rats,and explore the mechanism so as to provide experimental and theoretical evidence for preventing and treating Adriamycin Induced Cardiomyopathy. Methods:45 male Sptague-Dawley(SD) rats were randomly divided into 3 groups of 15 animials each:control groups;Adriamycin(ADR) group and Adriamycin(ADR) plus 3-Methyladenine(ADR+3-MA) group.Adriamycin(ADR) group:ADR was given at a dose of 4mg/kg by intraperitoneal injection(i.p) for every week,from second day of experiment and up to the cumulative dose of 24mg/kg for 6 weeks;ADR+3-MA group:the same dose of ADR was injected,and 500nmol(5ul)3-MA was give by i.p 3 hours beforeeach ADR injection;in control groups,instead of ADR and ADR+3-MA group,the same volume of physiology saline was injected.At 6th weekend after the beginning of experiment,transthoracic echocardiography(TTE)was applied to measure the heart funtion indices such as the left ventricular dimensions,volumes and thickness;draw-off blood from hearts to detected the malondialdehyde(MDA) level of serum and the reduced glutathione(GSH) level of blood by spectrophotography;Batches of 3 rats were killed 6th weekend after the beginning of experiment,calculated the heart weight index(HWI),the tissue sample were taken from the left ventricle wall.The sample was stained with hematoxylin and eosin(HE) and examined with a light microscope,and a part of sample were observed the morphous and the quantity of the autophagsome by electron microscope;expressions of Beclin-1 of myocardium was detected by west-bloting,and the level of LC3 of myocardium,was detected by immunohistochemistry.All the date were analyzed using the software SPSS11.5.
Results:1.The heart funtion of the left ventricular of ADR group were significant decreased compared with the control group,P<0.05;The heart weight index(HWI) of ADR group were significant increased compared with the control group,P<0.05;
2.The malondialdehyde(MDA) level of serum of ADR group were significant decreased compared with the control group,P<0.05;the GSH level of blood of ADR group were significant increased compared with the control group,P<0.05;
3.The expressions of Beclin-1 in myocardium of ADR group were significant increased compared with the control group and ADR+3-MA group,P<0.05;
4.The level of LC3 in myocardium of ADR group were significant increased compared with the control group and ADR+3-MA group,P<0.05;
5.Correlation analysis:there was a significant positive correlation between expressions of Beclin-1 and level of LC3.
Conclusion:1.The expressions of Beclin-1 in myocardium were up-regulated by Adriamycin and it can induced autophagy,and then induced cardiomyopathy.
2.The level of LC3 in myocardium were inseased in Adriamycin Induced cardio- myopathy,and there was a significant positive correlation between expressions of Beclin-1 and level of LC3.
3.To be an other form of programmed cell death(PCD) excepted Necrosis and Apoptosis,autophagy seemed to play an important role in Adriamycin Induced Cardiomyopathy,and can be inhibited by the 3-Methyladenine(3-MA).
方法:雄性(Sprague-Dawley)SD大鼠45只,体重在180～200克之间,随机分为3组,阿霉素(ADR)组(N=15),阿霉素(ADR)+3-甲基腺嘌呤(3-Methyladenine,3-MA)组(N=15),对照组(N=15)。阿霉素(ADR)组:实验的第二天起腹腔注射阿霉素4mg/kg,每周一次,共6周,累计剂量24mg/kg;阿霉素(ADR)+3-甲基腺嘌呤(3-MA)组:实验的第二天起腹腔注射同等剂量的阿霉素,在注射前半小时腹腔注射自噬抑制剂3-甲基腺嘌呤(3-MA)500nmol(5ul);对照组:腹腔注射等量的生理盐水。实验第六周末大鼠称重并心脏彩超测量左室收缩功能(射血分数EF及缩短分数FS),心脏取血分光光度法检测血浆中丙二醛(malondialdehyde,MDA)及全血中还原型谷胱甘肽(reduced glutathione,GSH)含量,取心脏并称重后计算心脏重量指数(heart weight index,HWI),取左心室心肌标本,HE(hematoxylin and eosin)染色观察心肌病理改变,电镜观察自噬体形态及数量,免疫印迹法(west-blotting)检测心肌组织中自噬基因Beclin-1的含量,免疫组化S-P法测定心肌细胞微管相关蛋白(Microtubule-associate Protein 1Light Chain 3,LC3)含量。所有数据均采用SPSS11.5统计软件进行统计分析。
结果:1、ADR组大鼠左室收缩功能较对照组下降,P＜0.05,具统计学意义;ADR组大鼠心脏重量指数(HWI)较对照组增高,P＜0.05,具统计学意义;
2、ADR组血浆MDA含量较对照组增高,P＜0.05,具统计学意义,ADR组全血GSH含量较对照组减低,P＜0.05,具统计学意义;
3、免疫印迹法显示:ADR组心肌组织中Beclin-1水平较对照组及ADR+3-MA组增高,P＜0.05,具统计学意义;
4、免疫组织化学染色显示:ADR组心肌组织中LC3含量较对照组及ADR+3-MA组增高,P＜0.05,具统计学意义;
5、直线相关分析:自噬基因Beclin-1水平与微管相关蛋白LC3含量呈显著正相关。
结论:1、阿霉素可引起大鼠心肌组织中自噬基因Beclin-1水平上调,从而诱导心肌自噬性程序性细胞死亡,导致心肌病变的发生。
2、阿霉素心肌病大鼠心肌细胞中微管相关蛋白LC3含量明显增高,且与自噬基因Beclin-1水平呈显著正相关。
3、自噬性程序性细胞死亡(Autophagy)作为除坏死及调亡以外的另一种程序性细胞死亡方式(programmed cell death,PCD)参与了阿霉素心肌病的发病,并可被自噬抑制剂3-MA抑制。
Objective:To explore the expression and significance of autophagy-related gene Beclin-1 and Microtubule-associated Protein 1 Light Chain 3(LC3) in Adriamycin Induced Cardiomyopathy in rats,prove that Autophagy take part in the development of Adriamycin Induced Cardiomyopathy in rats,and explore the mechanism so as to provide experimental and theoretical evidence for preventing and treating Adriamycin Induced Cardiomyopathy. Methods:45 male Sptague-Dawley(SD) rats were randomly divided into 3 groups of 15 animials each:control groups;Adriamycin(ADR) group and Adriamycin(ADR) plus 3-Methyladenine(ADR+3-MA) group.Adriamycin(ADR) group:ADR was given at a dose of 4mg/kg by intraperitoneal injection(i.p) for every week,from second day of experiment and up to the cumulative dose of 24mg/kg for 6 weeks;ADR+3-MA group:the same dose of ADR was injected,and 500nmol(5ul)3-MA was give by i.p 3 hours beforeeach ADR injection;in control groups,instead of ADR and ADR+3-MA group,the same volume of physiology saline was injected.At 6th weekend after the beginning of experiment,transthoracic echocardiography(TTE)was applied to measure the heart funtion indices such as the left ventricular dimensions,volumes and thickness;draw-off blood from hearts to detected the malondialdehyde(MDA) level of serum and the reduced glutathione(GSH) level of blood by spectrophotography;Batches of 3 rats were killed 6th weekend after the beginning of experiment,calculated the heart weight index(HWI),the tissue sample were taken from the left ventricle wall.The sample was stained with hematoxylin and eosin(HE) and examined with a light microscope,and a part of sample were observed the morphous and the quantity of the autophagsome by electron microscope;expressions of Beclin-1 of myocardium was detected by west-bloting,and the level of LC3 of myocardium,was detected by immunohistochemistry.All the date were analyzed using the software SPSS11.5.
Results:1.The heart funtion of the left ventricular of ADR group were significant decreased compared with the control group,P<0.05;The heart weight index(HWI) of ADR group were significant increased compared with the control group,P<0.05;
2.The malondialdehyde(MDA) level of serum of ADR group were significant decreased compared with the control group,P<0.05;the GSH level of blood of ADR group were significant increased compared with the control group,P<0.05;
3.The expressions of Beclin-1 in myocardium of ADR group were significant increased compared with the control group and ADR+3-MA group,P<0.05;
4.The level of LC3 in myocardium of ADR group were significant increased compared with the control group and ADR+3-MA group,P<0.05;
5.Correlation analysis:there was a significant positive correlation between expressions of Beclin-1 and level of LC3.
Conclusion:1.The expressions of Beclin-1 in myocardium were up-regulated by Adriamycin and it can induced autophagy,and then induced cardiomyopathy.
2.The level of LC3 in myocardium were inseased in Adriamycin Induced cardio- myopathy,and there was a significant positive correlation between expressions of Beclin-1 and level of LC3.
3.To be an other form of programmed cell death(PCD) excepted Necrosis and Apoptosis,autophagy seemed to play an important role in Adriamycin Induced Cardiomyopathy,and can be inhibited by the 3-Methyladenine(3-MA).
引文
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