赵丽, 陈昕. Keap-1/Nrf2/HO-1通路在曲美他嗪抑制顺铂诱导大鼠心肌损伤作用的研究[J]. 中国肿瘤临床, 2021, 48(16): 815-819. DOI: 10.12354/j.issn.1000-8179.2021.20210438
引用本文: 赵丽, 陈昕. Keap-1/Nrf2/HO-1通路在曲美他嗪抑制顺铂诱导大鼠心肌损伤作用的研究[J]. 中国肿瘤临床, 2021, 48(16): 815-819. DOI: 10.12354/j.issn.1000-8179.2021.20210438
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Li Zhao, Xin Chen. Effect of Keap-1/Nrf2/HO-1 pathway on inhibition of cisplatin induced myocardial injury in rats by trimetazidine[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2021, 48(16): 815-819. DOI: 10.12354/j.issn.1000-8179.2021.20210438
Citation: Li Zhao, Xin Chen. Effect of Keap-1/Nrf2/HO-1 pathway on inhibition of cisplatin induced myocardial injury in rats by trimetazidine[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2021, 48(16): 815-819. DOI: 10.12354/j.issn.1000-8179.2021.20210438
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Keap-1/Nrf2/HO-1通路在曲美他嗪抑制顺铂诱导大鼠心肌损伤作用的研究

Effect of Keap-1/Nrf2/HO-1 pathway on inhibition of cisplatin induced myocardial injury in rats by trimetazidine

    摘要
  • 摘要:
      目的  研究曲美他嗪（trimetazidine，TMZ）减轻顺铂(cisplatin)诱导的大鼠心肌细胞损伤，并通过抑制Keap-1调控Nrf2/HO-1起到心脏保护作用。
      方法  分离大鼠心肌细胞，分成三组，对照组、顺铂处理组（200 μM）和顺铂（200 μM）+TMZ（200 μM）处理组。检查细胞活力和ROS的含量，Western blot及Real-time PCR方法检测Nrf2及其上游Keap-1和下游HO-1的表达。
      结果  TMZ明显减轻顺铂对心肌细胞活力的抑制（P<0.01）。TMZ预处理均能有效地抑制活性氧物质ROS（P<0.01）的水平。Western blot结果显示，TMZ预处理可明显降低Nrf2的表达（P<0.01），抑制Keap-1的蛋白表达（P<0.01），增强抗氧化酶类靶蛋白如血红素氧合酶 1（hemo oxygenase 1，HO-1）的蛋白表达水平（P<0.01）。Real-time PCR结果显示，与对照组相比，顺铂处理的Nrf2表达显著增加（P<0.0001），TMZ预处理明显促进了Nrf2的核易位（P<0.01）；顺铂显著促进Keap-1（P<0.0001）和HO-1的表达（P<0.0001），TMZ进行预处理可显著抑制Keap-1的表达（P<0.0001），显著增强HO-1的表达水平（P<0.001）。
      结论  TMZ抑制了顺铂引起的心脏损伤，部分依赖于Keap-1/Nrf2/HO-1信号通路的抗氧化防御作用，显示出TMZ具有心脏保护作用，可作为抗氧化剂治疗化疗药物引起的心脏损伤。

     

    Abstract:
      Objective  To study the effect of trimetazidine (TMZ) in reducing rat myocardial injury induced by cisplatin and the cardioprotective effect of Nrf2/HO-1 by inhibiting Keap-1.
      Methods  Rat myocardial cells were isolated and divided into three groups: control group, cisplatin treated group (200 μM), and cisplatin +TMZ (200 μM) treated group. Cell viability and production of reactive oxygen species (ROS) were examined. Western blot and Real-time PCR were used to detect the expression of Nrf2, its upstream Keap-1, and downstream HO-1.
      Results  TMZ reduced the inhibitory effect of cisplatin on cardiomyocyte activity (P<0.01). TMZ pretreatment could effectively inhibit ROS production (P<0.01). Western blot results showed that TMZ pretreatment increased the expression of Nrf2 (P<0.01), inhibited the expression of Keap-1 (P<0.01), and enhanced HO-1 expression level (P<0.01). Compared with the control group, Real-time PCR revealed that the expression of Nrf2 was significantly increased by cisplatin treatment (P<0.0001), and TMZ pretreatment promoted the nuclear translocation of Nrf2 (P<0.01). Cisplatin significantly promoted the expression of Keap-1 (P<0.0001) and hemo oxygenase 1 (HO-1) (P<0.0001). TMZ pretreatment significantly inhibited the expression of Keap-1 (P<0.0001) and significantly enhanced the expression of HO-1 (P<0.001).
      Conclusions  TMZ significantly inhibited the myocardial injury induced by cisplatin, in part owing to the Keap-1/Nrf2/HO-1 associated antioxidant defense system. The findings suggest that TMZ has a cardioprotective effect as an antioxidant for the treatment of myocardial injury induced by chemotherapeutic drugs.

     

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