| | | PDTC对压力负荷过度诱导小鼠心肌肥大的防护作用及其机制研究
| | 制药论文【摘要】 目的制药论文 观察吡咯烷二硫基甲酸盐（PDTC）对心肌肥大发生发展的制药论文影响并探讨其机制。方法 以缩窄小鼠主动脉弓(TAC)诱导的心肌肥大为模型，观察PDTC对心肌肥大发生发展的影响，并采用EMSA检测心肌组织中NF-κB结合活性，应用Western blot方法分析心肌组织中phospho-GSK3β的表达水平。结果 (1)缩窄小鼠主动脉弓2周后，心脏重量/体重比值与假手术组相比增高48.7% (P＜0.01)，而且肥大心肌组织中NF-κB结合活性和phospho-GSK3β(Ser9)蛋白表达明显高于假手术组(P＜0.01)。(2)PDTC可明显减轻TAC诱导的心肌肥大，与TAC模型组相比可以使小鼠心脏重量/体重比值下降16.4%(P＜0.05)。PDTC可抑制心肌组织中NF-κB活性，与TAC模型组相比降低了34.3%(P＜0.01)，同时亦可抑制心肌组织中GSK3β(Ser9)磷酸化水平，p-GSK3β(Ser9)/ GSK3β比TAC模型组降低了22.1%(P＜0.05)。结论 PDTC可以通过抑制NF-κB结合活性和GSK3β（Ser9）磷酸化水平延缓心肌肥大的发生发展。
【关键词】 心肌肥大；吡咯烷二硫基甲酸盐；核因子κB； 糖原合成激酶-3β
【Abstract】 Objective To investigate the role and mechanism of PDTC on the development of cardiac hypertrophy in vivo.Methods PVB/N mice were employed and cardiac hypertrophy was induced by transverse aortic constriction for 2 weeks.Electrophoretic mobility shift assay (EMSA) was used to determine NFkB binding activity with nuclear proteins extracted from heart tissues； Western blots were performed to examine the phosphorylation of GSK-3β. In a separate experiment， PDTC was administered into mice subjected to transverse aortic constriction for 2 weeks.Results (1)Transverse aortic constriction(TAC) significantly increased the ratio of HW/BW. Two weeks after TAC， the ratio of HW/BW was significantly increased by 48.7%(P＜0.01)， compared to age-matched sham control. NFkB binding activity and the level of phospho- GSK-3β(Ser9) were significantly increased at 2 weeks following TAC compared to age-matched sham control (P＜0.01).(2)Administration of PDTC into TAC mice for 2 weeks， significantly reduced the ratio of HW/BW by 16.4%(P＜0.05)， compared to non-treated TAC mice. NFkB binding activity was significantly reduced by 34.3% (P＜0.01) in the hearts administered with PDTC for 2 weeks， compared to non-treated TAC group. In addition，administration of PDTC also decreased the level of phospho- GSK-3β(Ser9)/ GSK-3β by 22.1%(P＜0.05) compared to non-treated TAC group.Conclusion PDTC inhibit the NFkB binding activity and the level of phospho- GSK-3β(Ser9) in hypertrophic heart tissues and thereby attenuates the development of cardiac hypertrophy.
【Key words】 cardiac hypertrophy；pyrrolidine dithiocarbamate；NF-κB；GSK-3β
心肌肥大是心脏对生物机械牵张和神经体液刺激的一种主要反应。虽然早期心肌肥大是心脏维持有效心输出量的一种代偿性机制，但持久的心肌肥大会导致心脏进入失代偿阶段，继而发生不可逆转的心肌肥大和扩张，心肌收缩力下降，导致心力衰竭［1，2］。调控心肌细胞肥大的详细分子机制及关键的信号转导通路迄今尚未阐明。最近的研究提示核因子-κB（nuclear factor kappa B，NF-κB）信号通路可能在心肌肥大的发生发展中起着重要作用［2，3］。吡咯烷二硫基甲酸盐（pyrrolidine dithiocarbamate ，PDTC）是NF-κB抑制剂，通过其抗氧化作用可抑制肿瘤坏死因子（tumor necrosis factor，TNF）诱导的反应性氧自由基的产生和NF-κB活性［4］。Dechend等也报道抗氧化剂可通过抑制NF-κB活性而解除AngⅡ所诱导的心肌细胞肥大性反应［5］。然而，Hayakawa等报道PDTC抑制NF-κB活性与抗氧化功能无关［6］。为此，本研究以压力负荷增加诱导的小鼠心肌肥大为模型，进一步探讨PDTC抑制NF-κB活性的机制，并观察PDTC对心肌肥大发生发展的影响。
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