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艾司氯胺酮通过糖原合成酶激酶-3β/NOD样受体热蛋白结构域蛋白3通路改善新生鼠缺氧缺血性心肌损伤的研究

Esketamine improves hypoxic-ischemic myocardial injury in neonatal rats by glycogen synthase kinase-3β/NOD-like receptor thermal protein domain-containing protein 3 pathway

    摘要
  • 摘要:
    目的  基于糖原合成酶激酶-3β/NOD样受体热蛋白结构域蛋白3(GSK-3β/NLRP3)通路探讨艾司氯胺酮对新生鼠缺氧缺血性心肌损伤的作用。
    方法  将30只新生大鼠随机分为假手术组、模型组及艾司氯胺酮组, 每组10只。假手术组新生鼠行颈部正中切口，暴露双侧颈总动脉; 模型组和艾司氯胺酮组新生鼠采用结扎颈总动脉联合低氧环境建立缺血缺氧模型; 艾司氯胺酮组新生鼠给予艾司氯胺酮干预(50 mg/kg)。检测各组新生鼠左心室射血分数(LVEF)、左心室短轴缩短率(LVFS)、左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD)、血清肌酸激酶同工酶(CK-MB)、肌钙蛋白I(cTnI)、乳酸脱氢酶(LDH)、肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-6、IL-1β水平，心肌损伤、心肌细胞凋亡及凋亡蛋白半胱氨酸蛋白酶1/3/9(caspase 1/3/9)水平，心肌组织中性粒细胞浸润情况，以及心肌组织中GSK-3β、NLRP3蛋白水平变化。
    结果  相比于假手术组，模型组新生鼠LVEF、LVFS降低，LVEDD、LVESD增高，且艾司氯胺酮组新生鼠LVEF、LVFS高于模型组, LVEDD、LVESD低于模型组，差异均有统计学意义(P < 0.05)。模型组血清CK-MB、cTnI、LDH、TNF-α、IL-6、IL-1β水平，心肌损伤及凋亡，心肌组织切割的caspase 1/3/9蛋白水平、中性粒细胞数量、GSK-3β、NLRP3蛋白水平增加，且艾司氯胺酮组上述指标低于模型组，差异有统计学意义(P < 0.05)。
    结论  艾司氯胺酮通过抑制炎症反应改善新生鼠缺氧缺血性心肌损伤，其作用机制与GSK-3β/NLRP3通路有关。

     

    Abstract:
    Objective  To investigate the effects of esketamine on hypoxic-ischemic myocardial injury in neonatal rats based on glycogen synthase kinase-3β/NOD-like receptor thermal protein domain-containing protein 3 (GSK-3β/NLRP3) pathway.
    Methods  Thirty neonatal rats were randomly divided into sham operation group, model group and esketamine group, with 10 rats in each group. The rats in the sham operation group underwent a median incision in the neck to expose the bilateral common carotid arteries; the rats in the model group and the esketamine group underwent ligation of the common carotid arteries combined with a hypoxic environment to establish a model ofischemia and hypoxia; the rats in the esketamine group were given esketamine intervention (50 mg/kg). Left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), serum creatine kinase isoenzyme (CK-MB), cardiac troponin I (cTnI), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β levels, myocardial injury, myocardial cell apoptosis and apoptosis protein caspase 1/3/9 levels, neutrophil infiltration in myocardial tissue, and changes in GSK-3β and NLRP3 protein levels in myocardial tissue were detected in each group.
    Results  Compared with the sham operation group, the LVEF and LVFS were significantly decreased and the LVEDD and LVESD were significantly increased in the model group, while the LVEF and LVFS were significantly higher and the LVEDD and LVESD were significantly lower in the esketamine group than in the model group (P < 0.05). The serum levels of CK-MB, cTnI, LDH, TNF-α, IL-6, IL-1β, myocardial injury and apoptosis, caspase 1/3/9 protein levels in myocardial tissue sections, neutrophil counts, and GSK-3β and NLRP3 protein levels were significantly increased in the model group, and these indicators were significantly lower in the esketamine group than in the model group (P < 0.05).
    Conclusion  Esketamine improves hypoxic-ischemic myocardial injury in neonatal rats by inhibiting inflammation, and its mechanism of action is related to the GSK-3β/NLRP3 pathway.

     

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