右美托咪啶对大鼠缺血再灌注损伤心肌的保护作用及机制

Studies showed that myocardial ischemia reperfusion injury is the main cause of cardiovascular adverse events. The inflammatory reaction of myocardial is an important factor of ischemia reperfusion injury,and the TLR receptor is involved in the inflammatory response by activation of the MyD88, IRAK-1 pathway. Dexmedetomidine is a highly selective α2 adrenergic receptor agonist, has the effects of anti-inflammatory and organ protection. Our previous studies demonstrated that dexmedetomidine use can improve the survival rate in patients undergoing cardiac surgery and reduce the incidence of cardiovascular adverse events, also can inhibit the inflammatory reaction in rat brain by the pathway of the TLR4 receptor. But if dexmedetomidine could inhibit inflammatory reaction in myocardial and its mechanism is unclear.Therefore, we hypothesized that dexmedetomidine may alleviate the ischemia reperfusion injury by inhibiting the myocardial inflammatory reaction through the ways of activating the PI3K/Akt kinase, and inhibiting the expression of TLR4 receptor, regulation of the downstream signal molecules and reduce the apoptosis. In this study, we will apply MP-100A-CE analog-digital conversion , genetic engineering and molecular biology techniques under the conditions of the in vitro and in vivo experiment from the molecular, cellular and macroscopic levels. The aim of this research is to further exploring the protective effect and mechanism of dexmedetomidine on myocardial ischemia reperfusion injury in rats.The long term goal of this proposal is to provide a theoretical basis for reducing perioperative cardiovascular events.

研究表明心肌缺血-再灌注损伤是发生心血管事件的主要原因，而心肌炎症反应是缺血-再灌注损伤的重要原因之一，Toll样受体(TLR)通过活化MyD88、IRAK-1等途径参与了此炎症反应。右美托咪啶是一种高选择性α2肾上腺素能受体激动剂，具有抗炎及器官保护作用。我们前期的研究证实：右美托咪啶可以提高心脏手术患者的生存率及降低心脑血管等不良事件的发生，并通过TLR4受体抑制鼠脑内炎症反应。但右美托咪啶是否能抑制心肌炎症反应及其机制尚不清楚。因此，我们推测右美托咪啶可能通过激活PI3K/Akt激酶，同时通过抑制TLR4受体表达，调控下游信号分子，抑制局部炎症反应和细胞凋亡来减轻心肌缺血再灌注损伤。本课题拟结合离体和在体实验，采用MP-100A-CE 模数转换、基因工程及分子生物学技术等方法，从分子、细胞和整体来探讨右美托咪啶对大鼠缺血再灌注损伤心肌的保护作用及机制，为围手术期心肌保护提供理论依据。

Dex是一种高选择性 α2肾上腺素受体激动药，它具有抗炎及器官保护的作用。本项目研究旨在探讨右美托咪定对缺血再灌注损伤心肌的保护作用及其机制。研究结果表明：Dex预处理能够显著减轻I/R诱导的心脏损伤，减小心肌梗死面积，降低血清心肌肌钙蛋白的分泌，并显著抑制心肌组织HMGB1-TLR4/MyD88-NF-κB信号以及降低心肌组织IL-6和TNF-α的分泌水平；通过细胞实验，我们发现siRNA-TLR4通过减少炎症因子的释放减轻缺氧复氧诱导的心肌细胞损伤, TLR4基因过表达显著降低Dex对缺氧复氧诱导的心肌细胞损伤的保护作用；通过动物实验，我们发现AAV-HMGB1过表达通过调控TLR4/MyD88-NF-κB信号以及炎症因子的释放显著抑制Dex对大鼠心肌的保护作用；进一步证明单侧迷走神经切断术或给予α7烟碱乙酰胆碱受体抑制剂甲基牛扁碱可通过调控HMGB1信号部分逆转Dex对大鼠心肌I/R损伤的保护作用。综上，Dex预处理通过抑制HMGB1-TLR4 / MyD88-NF-κB信号转导和激活胆碱能抗炎途径来保护心肌，该研究为Dex在心脏病患者围手术期的临床应用提供了理论依据。

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