右美托咪定诱导的心肌缺血再灌注损伤中的心脏保护作用是通过抑制高迁移率族蛋白 1 及胆碱能抗炎通路介导的。

Dexmedetomidine-induced cardioprotection is mediated by inhibition of high mobility group box-1 and the cholinergic anti-inflammatory pathway in myocardial ischemia-reperfusion injury.

机构信息

Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.

Department of Pathology, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou Science and Technology Town Hospital, Suzhou, China.

出版信息

PLoS One. 2019 Jul 25;14(7):e0218726. doi: 10.1371/journal.pone.0218726. eCollection 2019.

OBJECTIVES

Dexmedetomidine (DEX) is a selective α2-adrenoceptor agonist that has anti-inflammatory and cardioprotective effects in myocardial ischemia/reperfusion (I/R) injury. The present study aimed to investigate the underlying mechanism by which DEX protects against myocardial I/R.

METHODS

Sprague Dawley rats were subjected to either sham operation or myocardial I/R, which was induced by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. Rats were treated with either DEX or saline prior to surgery. We measured heart infarct size, serum cardiac Troponin I (cTnI), cardiac High mobility group box-1 (HMGB1) expression, myocardial apoptosis and cytokine production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Besides, we evaluated the heart function at 4 weeks post-reperfusion by echocardiography. Unilateral vagotomy or inhibition of the α7 nicotinic acetylcholine receptor (α7nAChR) with methyllycaconitine (MLA) was applied to investigate whether DEX-induced cardioprotection is mediated via the cholinergic anti-inflammatory pathway. Cardiac-selective overexpression of HMGB1 was administered to further confirm if HMGB1 is a key anti-inflammatory target during DEX-induced cardioprotection.

RESULTS

DEX pretreatment significantly attenuated I/R-induced cardiac damage, as evidenced by decreases in short-term injury indicators including myocardial infarct size, cTnI release, myocardial apoptosis, cardiac HMGB1 expression, IL-6 and TNF-α production, as well as improvement on long-term cardiac function at 4 weeks post-reperfusion. These effects were partially reversed by either unilateral vagotomy or methyllycaconitine treatment. Besides, cardiac HMGB1-overexpression nearly abolished DEX-induced cardioprotection.

CONCLUSIONS

DEX pretreatment protects against myocardial I/R by inhibiting cardiac HMGB1 production and activating the cholinergic anti-inflammatory pathway.

目的

右美托咪定（DEX）是一种选择性α2-肾上腺素受体激动剂，在心肌缺血/再灌注（I/R）损伤中具有抗炎和心脏保护作用。本研究旨在探讨 DEX 保护心肌 I/R 的潜在机制。

方法

Sprague Dawley 大鼠接受假手术或心肌 I/R，结扎左前降支 30 分钟后再灌注 120 分钟。手术前大鼠给予 DEX 或生理盐水治疗。我们测量了心肌梗死面积、血清心肌肌钙蛋白 I（cTnI）、心脏高迁移率族蛋白 B1（HMGB1）表达、心肌细胞凋亡和白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的细胞因子产生。此外，通过超声心动图在再灌注后 4 周评估心脏功能。应用单侧迷走神经切断术或烟碱型乙酰胆碱受体 7 型（α7nAChR）抑制剂甲基六氢吡啶（MLA）来研究 DEX 诱导的心脏保护是否通过胆碱能抗炎途径介导。给予心脏选择性过表达 HMGB1，进一步证实 HMGB1 是否是 DEX 诱导的心脏保护中的关键抗炎靶点。

结果

DEX 预处理显著减轻了 I/R 引起的心脏损伤，表现在短期损伤指标的降低，包括心肌梗死面积、cTnI 释放、心肌细胞凋亡、心脏 HMGB1 表达、IL-6 和 TNF-α的产生，以及再灌注后 4 周的长期心脏功能改善。这些作用部分被单侧迷走神经切断术或 MLA 治疗逆转。此外，心脏 HMGB1 过表达几乎消除了 DEX 诱导的心脏保护作用。