CPU86017及其旋光异构体对L-甲状腺素致大鼠心肌病异常的calcineurin和NFκB基因表达的抑制作用

中国临床药理学与治疗学 ›› 2006, Vol. 11 ›› Issue (4): 392-397.

CPU86017及其旋光异构体对L-甲状腺素致大鼠心肌病异常的calcineurin和NFκB基因表达的抑制作用

齐敏友, 夏绘晶, 戴德哉, 汤晓赟, 苏蔚, 张灿¹

中国药科大学药理研究室, ¹新药中心, 南京210009, 江苏

收稿日期:2005-12-14 接受日期:2006-04-10 出版日期:2006-04-26 发布日期:2020-12-08

CPU86017 and its enantiomers inhibit abnormal gene expression of calcineurin and NFκB in rat cardiomyopathy induced by L-thyroxin

QI Min-you, XIA Hui-jing, DAI De-zai, TANG Xiao-yun, SU Wei, ZHANG Can¹

Research Division of Pharmacology;¹Center of New Drug Research &Development, China Pharmaceutical University, Nanjing 210009, Jiangsu, China

Received:2005-12-14 Accepted:2006-04-10 Online:2006-04-26 Published:2020-12-08
Contact: DAI De-zai, male, professor, engaged in cardiovascular pharmacology. Tel:025-83271270 　E-mail:dezaidai@vip.sina.com
About author:QI Min-you, male, Ph.D candidate, engaged in cardiovascular pharmacology. Tel:025-83271453 　E-mail:qiminyou@163.com
Supported by:
This project was supported by the Foundation of Natural Science of Jiangsu (BK2002120) and a key projected from National Foundation of Natural Science of China (№30230170).

摘要/Abstract

摘要： 目的:研究CPU86017 及其旋光异构体对L-甲状腺素致大鼠心肌病异常的calcineurin 和NFκB基因改变, 并比较CPU86017 及其旋光异构体对它们的作用。方法:大鼠随机分成7 组, 每日给予L-甲状腺素(0.2 mg·kg^-1, sc) 共10 d 造成心肌病模型,CPU86017 及其旋光异构体(SR 、SS 、RS 、RR)(4 mg·kg^-1, sc) 在d 6 连续给药5 d。动物处死后测定心脏指数, 取大鼠心脏测定心肌组织中氧化应激指标, NO 和iNOS 的活力, 大鼠左心室心肌Calcineurin、NF-κB 的基因表达由半定量逆转录酶PCR 方法测定。结果:L-甲状腺素致大鼠心肌病模型组心肌明显肥大, 氧化应激增强, NO 含量减少, iNOS 活力增强, Calcineurin 和NF-κB 基因表达上调。给予CPU86017 及其旋光异构体能不同程度地改善心肌中NO 含量及iNOS 活力, 减轻氧化应激, 可以下调这些基因的表达, 其中SR 比其它旋光异构体疗效好。结论:Calcineurin 和NF-κB 可能对L-甲状腺素所致大鼠心肌病中细胞内钙调节起着重要的作用,CPU86017 及其旋光异构体SR 对L-甲状腺素所致大鼠心肌病具有保护作用, 该作用与抑制心肌Calcineurin、NF-κB 基因的表达、抑制NOS 及抗氧化有关。

关键词: CPU86017, 旋光异构体, L-甲状腺素, 心肌肥大, 钙调神经磷酸酶

Abstract: AIM: To investigate the CPU86017 and its enantiomers inhibit abnormal gene expression of calcineurin and NFκB in rat cardiomyopathy induced by L-thyroxin and compare the effect of CPU86017 (racemate) with its 4 enantiomers:(7S, 13R), (7S, 13S), (7R, 13S), and (7R, 13R)-CPU86017 in this model. METHODS: The animals were randomly divided into 7 groups.The rat hypertrophied model was produced by treatment with L-thyroxin 0.2 mg·kg ^-1 ·d ^-1, sc for 10 d and treated with CPU86017 or its enantiomers 4 mg·kg ^-1 ·d ^-1, sc from d 6 to d 10.The changes in left ventricular (LV) weight index, redox system, and the NO and iNOS activity in the myocardium were investigated.The expression of mRNA of calcineurin 、NF-κB in the left ventricle was measured.RESULTS: There were significant cardiac hypertrophy and oxidative stress in rats treated by L-thyroxin.The expression of calcineurin, NFκB mRNA were upregulated (P <0.05, compared with that of control).After treatment with CPU86017 (racemate and enantiomers), LV remodeling and the redox system were improved.CPU86017 and (7S, 13R)-CPU86017 showed a better improvement on LV remodeling and the redox than the other isomers and restored the normal expression of calcineurin, NF-κB (P <0.05, P <0.01), respectively.CONCLUSION: It suggested that an up-regulation of calcineurin and NFκB possibly related to the altered intracellular calcium handling system plays a role in the progression of L-thyroxin induced cardiomyopathy and CPU-86017 and its 7S, 13R-CPU86017 enantiomer effectively inhibit the abnormal expression of calcineurin and NFκB genes, the NOS enzyme and oxidant stress in the cardiomyopathy.

Key words: CPU86017, enantiomers, L-thyroxin, cardiac hypertrophy, calcineurin

中图分类号:

齐敏友, 夏绘晶, 戴德哉, 汤晓赟, 苏蔚, 张灿. CPU86017及其旋光异构体对L-甲状腺素致大鼠心肌病异常的calcineurin和NFκB基因表达的抑制作用[J]. 中国临床药理学与治疗学, 2006, 11(4): 392-397.

QI Min-you, XIA Hui-jing, DAI De-zai, TANG Xiao-yun, SU Wei, ZHANG Can. CPU86017 and its enantiomers inhibit abnormal gene expression of calcineurin and NFκB in rat cardiomyopathy induced by L-thyroxin[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2006, 11(4): 392-397.

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