AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2-dependent sudden cardiac death
AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2-dependent sudden cardiac death
复制标题
通过远程缺血预处理激活 AKT 和 ERK1/2 可预防 Kcne2 依赖性心源性猝死。
DOI：
10.14814/phy2.13957
复制
发表时间：
2019-02-01
影响因子：
2.5
通讯作者：
Abbott, Geoffrey W.
中科院分区：
文献类型：
--
作者：
Hu, Zhaoyang;Liu, Jin;Abbott, Geoffrey W.
心脏性猝死(SCD)是全球主要的死亡原因。SCD常由心肌缺血再灌注(IR)损伤、离子通道基因内的病理序列变异或两者的组合引起。需要其他方法来预防或改善与SCD相关的室性心律失常。在这里，我们研究了肢体和肝脏的远程缺血预适应(RIPC)在减少SCD小鼠模型室性心律失常方面的效果。缺乏Kcne2基因的小鼠通过冠状动脉结扎暴露于IR损伤，Kcne2基因编码与获得性长QT综合征相关的钾通道β亚基。这导致所有小鼠(15/15)在再灌流期间出现室性心律失常(15/15)和5/15小鼠发生SCD。值得注意的是，之前的RIPC(肢体或肝脏)极大地降低了所有室性心律失常的发生率和严重程度，并完全预防了SCD。生化和药理学分析表明，RIPC的心肌保护作用需要ERK1/2和/或AKT的磷酸化。缺乏GSK-3β磷酸化的改变提示了传统的再灌注损伤挽救激酶(Risk)信号通路的保护作用。如果在人类研究中复制，肢体RIPC可能代表着一种非侵入性、非药物方法，以限制与缺血和/或通道病变相关的SCD相关的危险室性心律失常。
Sudden cardiac death (SCD) is the leading global cause of mortality. SCD often arises from cardiac ischemia reperfusion (IR) injury, pathologic sequence variants within ion channel genes, or a combination of the two. Alternative approaches are needed to prevent or ameliorate ventricular arrhythmias linked to SCD. Here, we investigated the efficacy of remote ischemic preconditioning (RIPC) of the limb versus the liver in reducing ventricular arrhythmias in a mouse model of SCD. Mice lacking the Kcne2 gene, which encodes a potassium channel beta subunit associated with acquired Long QT syndrome were exposed to IR injury via coronary ligation. This resulted in ventricular arrhythmias in all mice (15/15) and SCD in 5/15 mice during reperfusion. Strikingly, prior RIPC (limb or liver) greatly reduced the incidence and severity of all ventricular arrhythmias and completely prevented SCD. Biochemical and pharmacological analysis demonstrated that RIPC cardioprotection required ERK1/2 and/or AKT phosphorylation. A lack of alteration in GSK-3 beta phosphorylation suggested against conventional reperfusion injury salvage kinase (RISK) signaling pathway protection. If replicated in human studies, limb RIPC could represent a noninvasive, nonpharmacological approach to limit dangerous ventricular arrhythmias associated with ischemia and/or channelopathy-linked SCD.