右美托咪定心脏保护效应的miRNA机制研究

Dexmedetomidine is a highly selective α2 adrenoreceptor agonist, which exhibits a wide range of effects, including sedation, analgesia, antianxiety, sympatholytic properties. As an anaesthetic adjuvant, it is widely used in operative processes and ICU sedation. Recently it has been demonstrated that it has cardioprotective effects, such as anti-ischemia/reperfusion injury, anti-arrhythmic and prevention of postoperative cardiac complications. On one hand, the mechanisms of anti-ischemia/reperfusion injury may be related to attenuating sympathetic activation, dropping heart rate, increasing oxygen supply while decresing the consumption, so that it can keep the myocardial oxygen balance; on the other hand, dexmedetomidine preconditioning is mediated by the activation of pro-survival signal pathway after cardiac α2 receptor stimulation. In addition, it can attenuate catecholamine release, make vagus nerve stimulation relatively, reduce the stress response caused by operation and anesthesia, which result in its anti-arrhythmic effect. Also, because of its pharmacological structure, imidazoline receptors play an important role in anti-arrhythmic. In general, the exact mechanisms of its cardioprotective effects are still unclear. Future researches need to aim at investigating the molecular and genetic mechanisms of its cardioprotective effects . We will investigate the molecular and genetic mechanisms of its cardioprotective effects at the system, organ, tissue, cellular and molecular levels.

右美托咪定为高选择性 α2受体激动剂，具有镇静、镇痛、抗焦虑、抑制交感神经兴奋等作用，现作为麻醉辅助药用于手术和 ICU 镇静。近期研究发现右美托咪定具有心脏保护作用，如抗缺血再灌注损伤、抗心律失常，从而总体上降低术后心脏相关并发症的发生。其抗缺血再灌注损伤作用机制一方面可能与抑制中枢的交感活性，降低心率、增加氧供、降低氧耗相关，另一方面可通过缺血预处理机制，激活相关促存活信号通路抗缺血再灌注损伤。同时，使用该药后儿茶酚胺释放减少，迷走神经相对兴奋，可降低手术及麻醉操作引起的应激反应，并可与咪唑啉受体结合，使其具有抗心律失常作用。总体而言，其保护作用的确切机制尚不明确，miRNAs 调节右美托咪定心脏保护的分子机制还不清楚。我们将从整体、器官、组织、细胞、分子水平深入研究miRNA调控右美托咪定心脏保护的分子机制。

背景：.非心脏手术围术期心血管事件是择期手术患者围术期并发症和病死率增加的重要原因。.方向：.右美托咪定具有抗心肌缺血再灌注损伤的作用，但miRNA 在DEX 心脏保护效应起的作用还没有研究。.主要内容：.右美托咪定预处理对离体和在体急性心梗大鼠心肌miRNA 表达谱的影响；右美托咪定预处理对缺氧复氧大鼠心肌细胞miRNA 表达谱的影响；鉴别并证实与右美托咪定有关的miRNA-665；过表达和低表达miRNA-665 对细胞凋亡率的影响；miRNA 靶点分析与验证；miRNA 细胞实验验证；miRNA 动物实验验证。 .重要结果：. 1.以离体大鼠心脏Langendorff灌注模型为研究对象，检测右美托咪定预处理大鼠离体心脏缺血/再灌注损伤心肌组织中差异表达的miRNAs的表达谱，与IR组相比，DP组心肌组织中中出现1个miRNA表达上调，2个miRNA表达下调。.2. 以在体大鼠心肌缺血再灌注损伤模型为对象，分析右美托咪定对在体大鼠心肌缺血再灌注损伤保护作用的miRNA差异表达谱，与IR组相比DP组共27个miRNA表达上调，共38个miRNA表达下调；.3.右美托咪定预处理可减少氧化应激引起的miR-665表达和凋亡，过表达miR-665可加重氧化应激引起的凋亡，miR-665敲除可减轻凋亡，而敲除AK1和Cnr2则促进凋亡。miR-665可抑制AK1和Cnr2表达。.关键数据：.右美托咪定预处理对离体和在体大鼠心脏缺血/再灌注损伤具有保护作用，其机制与右美托咪定引起心肌组织中miRNA差异表达有关。右美托咪定预处理可减少氧化应激引起的miR-665表达和凋亡，过表达miR-665可加重氧化应激引起的改变凋亡，miR-665敲除可减轻凋亡，而敲除AK1和Cnr2则促进凋亡。miR-665可抑制AK1和Cnr2表达。.科学意义：.本研究通过右美托咪定围术期心脏保护作用microRNA调控机制的研究，为右美托咪定的临床应用提供理论基础，为右美托咪定心脏保护作用的基础研究提供研究的新视角。