目的 探究右美托咪定（dexmedetomidine, Dex）预处理通过抑制铁死亡对小鼠心肌缺血再灌注损伤（myocardial ischemia reperfusion injury, MIRI）的影响和相关机制。 方法 健康SPF级雄性C57BL/6小鼠42只，6~8周龄，体重23~25 g，按随机数字表法分为3组（每组14只）：假手术组（Sham组）、缺血再灌注损伤组（IR组）、右美托咪定预处理组（Dex+IR组）。Sham组左冠状动脉前降支（left anterior descending coronary artery, LAD）只穿线，不结扎；IR组LAD结扎30 min，再灌注24 h；Dex+IR组缺血前30 min腹腔注射Dex 25 μg/kg，手术方法同IR组。伊文蓝和2，3，5‑氯化三苯基四氮唑（2, 3, 5‑triphenyl tetrazolium chloride, TTC）双染色法检测心肌缺血面积及心肌梗死面积，H‑E染色观察心肌组织形态变化，透射电镜观察心肌组织线粒体超微结构，比色法检测心肌组织中Fe2+、丙二醛（malondialdehyde, MDA）含量，Western blot法检测心肌组织中酰基辅酶A合成酶长链家族成员4（acyl‑CoA synthetase long chain family member 4, ACSL4）及谷胱甘肽过氧化物酶4（glutathione peroxidase 4, GPX4）蛋白水平。 结果 与Sham组比较：IR组和Dex+IR组心肌缺血面积和心肌梗死面积增加（P<0.05）；IR组心肌组织损伤严重，线粒体嵴减少甚至消失，Fe2+和MDA含量、ACSL4蛋白水平升高（P<0.05），GPX4蛋白水平降低（P<0.05）；Dex+IR组Fe2+含量升高（P<0.05）。与IR组比较，Dex+IR组心肌组织损伤及线粒体损伤显著改善，心肌梗死面积、Fe2+和MDA含量、ACSL4蛋白水平降低（P<0.05），GPX4蛋白水平升高（P<0.05）。 结论 Dex预处理可减轻铁死亡介导的MIRI，其机制可能与抑制ACSL4并激活GPX4有关。
Objective To investigate the effect of dexmedetomidine (Dex) pretreatment on myocardial ischemia reperfusion injury (MIRI) in mice through inhibiting ferroptosis. Methods A total of 42 healthy male SPF C57BL/6 mice, aged 6‒8 weeks, weighing 23‒25 g, were selected. According to the random number table method, they were divided into three groups (n=14): group Sham operation (group Sham), group ischemia reperfusion injury (group IR), and group Dex pretreatment with ischemia reperfusion injury (group Dex+IR). In group Sham, the left anterior descending coronary artery (LAD) was threaded without ligation. In group IR, LAD ligation was performed for 30 min followed by reperfusion for 24 h. Group Dex+IR was intraperitoneally injected with Dex at 25 μg/kg 30 min before ischemia, in addition to the same operation method as group IR. The ischemic area and infarct volume were measured by Evans blue and 2, 3, 5‑triphenyl tetrazolium chloride (TTC) double staining. Hematoxylin eosin staining was used to observe the pathological changes of myocardial tissue. The ultrastructure of the mitochondria in myocardial tissues was observed by transmission electron microscopy. Colorimetry was used to detect the contents of Fe2+ and malondialdehyde (MDA) in myocardial tissues. The levels of acyl‑CoA synthetase long chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4) were measured by Western blot. Results Compared with group Sham, the ischemic area and infarct volume increased in group IR and group Dex+IR (P<0.05); group IR showed severe pathological damage to myocardial tissues, with the mitochondrial cristae diminished or even eliminated, as well as remarkably increases in the contents of Fe2+ and MDA and ACSL4 levels (P<0.05), and decreases in GPX4 levels (P<0.05); the contents of Fe2+ increased in group Dex+IR (P<0.05). Compared with group IR, group Dex+IR presented remarkable improvement in pathological damage to myocardial tissue and mitochondrium, as well as decreases in infarct volume, the contents of Fe2+ and MDA, and ACSL4 levels (P<0.05), and increases in GPX4 levels (P<0.05). Conclusions Dex pretreatment can attenuate ferroptosis‑mediated MIRI, which may be related with inhibition of ACSL4 and activation of GPX4.
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