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盐酸戊乙奎醚对小鼠心肌缺血再灌注损伤的保护作用及机制
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| 篇名： | 盐酸戊乙奎醚对小鼠心肌缺血再灌注损伤的保护作用及机制 |
| TITLE： | Protective effects and mechanism of penehyclidine hydrochloride on myocardial ischemia-reperfusion injury in mice |
| 摘要： | 目的 基于巨噬细胞迁移抑制因子（MIF）/腺苷一磷酸活化的蛋白激酶（AMPK）信号通路探讨盐酸戊乙奎醚（PHC）对小鼠心肌缺血再灌注（I/R）损伤的保护作用及潜在机制。方法将雄性C57BL/6小鼠随机分为假手术组、I/R组、I/R+PHC组（PHC20μg/kg）、I/R+ISO-1组（MIF抑制剂35mg/kg）、I/R+PHC+ISO-1组（剂量同各单药组），每组8只。除假手术组外，其余各组均采用冠状动脉结扎法制备I/R损伤模型。于结扎前30min，各药物组小鼠分别单次尾静脉注射相应药液1mL。于再灌注120min后，检测各组小鼠的心功能指标[心率、每搏输出量、射血分数、心输出量、收缩期末左室后壁厚度（LVPWs）、舒张期末左室后壁厚度（LVPWd）]和血清中炎症因子[白细胞介素6（IL-6）、IL-10、肿瘤坏死因子α（TNF-α）]水平，观察其心肌组织病理改变和超微结构，并检测心肌组织中B细胞淋巴瘤2（Bcl-2）、磷酸化AMPKα（p-AMPKα）、MIF蛋白的表达水平。结果与假手术组比较，I/R组小鼠心肌细胞排列松散，炎症细胞浸润严重，线粒体受损明显，其血清中IL-6、TNF-α水平和心肌组织中p-AMPKα蛋白的表达均显著升高或上调，心率、每搏输出量、射血分数、心输出量、LVPWd和血清中IL-10水平均显著降低（P＜0.05）；与I/R组比较，I/R+PHC组小鼠心肌组织病变有所减轻，其血清中IL-6、TNF-α水平均显著降低，心率、每搏输出量、射血分数、心输出量、LVPWs、LVPWd、血清中IL-10水平以及心肌组织中Bcl-2、p-AMPKα、MIF蛋白的表达均显著升高或上调（P＜0.05）；而I/R+ISO-1组小鼠心肌组织病变有所加重，多数定量指标显著恶化（P＜0.05）；MIF抑制剂能普遍逆转PHC对I/R小鼠的保护作用（P＜0.05）。结论PHC可改善I/R小鼠心功能，减轻其心肌组织炎症，恢复其心肌组织超微结构，上述作用可能与激活MIF/AMPK信号通路有关。 |
| ABSTRACT： | OBJECTIVE To investigate the protective effects and potential mechanism of penehyclidine hydrochloride （PHC） on myocardial ischemia-reperfusion （I/R） injury in mice through the macrophage migration inhibitory factor （MIF）/adenosine monophosphate-activated protein kinase （AMPK） signaling pathways. METHODS Male C57BL/6 mice were randomly divided into sham operation group， I/R group， I/R+PHC group （PHC 20 μg/kg）， I/R+ISO-1 group （MIF inhibitor 35 mg/kg）， I/R+ PHC+ISO-1 group （with the same dosage as each single drug group）， with 8 mice in each group. Except for the sham operation group， the myocardial I/R injury model was prepared by coronary artery ligation. Thirty minutes before ligation， mice in each drug group were injected with 1 mL of the corresponding drug solution through the tail vein. After 120 min of reperfusion， the levels of cardiac function indexes [heart rate， stroke volume， ejection fraction， cardiac output， left ventricular posterior wall thickness in systole （LVPWs）， left ventricular posterior wall thickness in diastole （LVPWd）]， serum inflammatory factors [interleukin-6 （IL- 6）， IL-10， tumor necrosis factor-α （TNF-α）] in mice were detected in each group； the pathological changes and ultrastructure of myocardial tissue were observed， and the protein expressions of B cell lymphoma-2 （Bcl-2）， phosphorylated AMPKα （p-AMPKα） and MIF in myocardial tissue were detected. RESULTS Compared with the sham operation group， the myocardial cells in the I/R group were loosely arranged， with severe infiltration of inflammatory cells and obvious mitochondrial damage. Serum levels of IL-6 and TNF-α and protein expression of p-AMPKα in myocardial tissue were significantly increased or upregulated， while heart rate， stroke volume， ejection fraction， cardiac output， LVPWd and serum level of IL-10 were significantly decreased （P＜0.05）. Compared with the I/R group， the myocardial tissue lesions in the I/R+PHC group were alleviated； serum levels of IL-6 and TNF-α were decreased significantly， while heart rate， stroke volume， ejection fraction， cardiac output， LVPWs， LVPWd， serum level of IL-10， and protein expressions of Bcl-2， p- AMPKα and MIF in myocardial tissue were significantly increased or upregulated （P＜0.05）. However， myocardial tissue lesions of mice in the I/R+ISO-1 group worsened， with most quantitative indicators significantly deteriorating （P＜0.05）； MIF inhibitor could generally reverse the protective effect of PHC on I/R mice （P＜0.05）. CONCLUSIONS PHC can improve cardiac function， reduce myocardial inflammation， and restore the ultrastructure of myocardial tissue in I/R mice. These effects may be related to the activation of the MIF/AMPK signaling pathway. |
| 期刊： | 2024年第35卷第24期 |
| 作者： | 贾春媚；孟晨雪；张宝慧；韩帅；訾聪娜 |
| AUTHORS： | JIA Chunmei，MENG Chenxue，ZHANG Baohui，HAN Shuai，ZI Congna |
| 关键字： | 盐酸戊乙奎醚；心肌缺血再灌注；炎症反应；MIF/AMPK信号通路 |
| KEYWORDS： | penehyclidine hydrochloride； myocardial ischemia-reperfusion； inflammatory response； MIF/AMPK signaling |
| 阅读数： | 5 次 |
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