右美托咪定预处理通过激活α2-肾上腺素能受体抑制心肌自噬减轻大鼠心肌缺血/再灌注损伤。
Dexmedetomidine Preconditioning Attenuates Myocardial Ischemia/Reperfusion Injury in Rats by Suppressing Mitophagy Via Activating Α2-Adrenergic Receptor.
机构信息
Guizhou Aerospace Hospital, Zunyi, Guizhou - China.
Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou - China.
出版信息
Arq Bras Cardiol. 2023 Oct;120(10):e20220750. doi: 10.36660/abc.20220750.
BACKGROUND
Dexmedetomidine (DEX), a specific α2-adrenergic receptor agonist, is protective against myocardial ischemia/reperfusion injury (MIRI). However, the association between DEX preconditioning-induced cardioprotection and mitophagy suppression remains unclear.
OBJECTIVE
Hence, we aimed to investigate whether DEX preconditioning alleviates MIRI by suppressing mitophagy via α2-adrenergic receptor activation.
METHOD
Sixty isolated rat hearts were treated with or without DEX before inducing ischemia and reperfusion; an α2-adrenergic receptor antagonist, yohimbine (YOH), was also administered before ischemia, alone or with DEX. The heart rate (HR), left ventricular diastolic pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), maximal and minimal rate of left ventricular pressure development (±dp/dtmax), and myocardial infarction size were measured. The mitochondrial ultrastructure and autophagosomes were assessed using transmission electron microscopy. Mitochondrial membrane potential and reactive oxygen species (ROS) levels were measured using JC-1 and dichloride hydrofluorescein diacetate assays, respectively. The expression levels of the mitophagy-associated proteins Beclin1, LC3II/I ratio, p62, PINK1, and Parkin were detected by western blotting.
RESULTS
Compared with the control group, in the ischemia/reperfusion group, the HR, LVDP, and ±dp/dtmax were remarkably decreased (p< 0.05), whereas LVEDP and infarct sizes were significantly increased (p< 0.05). DEX preconditioning significantly improved cardiac dysfunction reduced myocardial infarction size, maintained mitochondrial structural integrity, increased mitochondrial membrane potential, inhibited autophagosomes formation, and decreased ROS production and Beclin1, LC3II/I ratio, PINK1, Parkin, and p62 expression(p< 0.05). When DEX and YOH were combined, YOH canceled the effect of DEX, whereas the use of YOH alone had no effect.
CONCLUSION
Therefore, DEX preconditioning was cardioprotective against MIRI in rats by suppressing mitophagy via α2-adrenergic receptor activation.
背景
右美托咪定（DEX）是一种特定的α2-肾上腺素能受体激动剂，可对抗心肌缺血/再灌注损伤（MIRI）。然而，DEX 预处理诱导的心脏保护作用与自噬抑制之间的关系尚不清楚。
目的
因此，我们旨在研究 DEX 预处理是否通过激活α2-肾上腺素能受体来抑制自噬从而减轻 MIRI。
方法
在诱导缺血和再灌注之前，用或不用 DEX 处理 60 个分离的大鼠心脏；在缺血前，还单独或与 DEX 一起给予α2-肾上腺素能受体拮抗剂育亨宾（YOH）。测量心率（HR）、左心室舒张压（LVDP）、左心室舒张末期压（LVEDP）、左心室压力最大和最小发展速率（±dp/dtmax）以及心肌梗死面积。使用透射电子显微镜评估线粒体超微结构和自噬体。使用 JC-1 和二氯荧光素二乙酸酯测定法分别测量线粒体膜电位和活性氧（ROS）水平。通过 Western blot 检测自噬相关蛋白 Beclin1、LC3II/I 比值、p62、PINK1 和 Parkin 的表达水平。
结果
与对照组相比，在缺血/再灌注组中，HR、LVDP 和±dp/dtmax 明显降低（p<0.05），而 LVEDP 和梗死面积明显增加（p<0.05）。DEX 预处理显著改善心脏功能，减少心肌梗死面积，维持线粒体结构完整性，增加线粒体膜电位，抑制自噬体形成，减少 ROS 产生和 Beclin1、LC3II/I 比值、PINK1、Parkin 和 p62 的表达（p<0.05）。当 DEX 和 YOH 联合使用时，YOH 取消了 DEX 的作用，而单独使用 YOH 则没有作用。
结论
因此，DEX 预处理通过激活α2-肾上腺素能受体抑制自噬对大鼠 MIRI 具有心脏保护作用。
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