高胆固醇血症通过改变 MG53/RISK/GSK3β 信号通路阻断七氟醚预处理诱导的心肌缺血再灌注损伤的保护作用。

Hypercholesterolemia blocked sevoflurane-induced cardioprotection against ischemia-reperfusion injury by alteration of the MG53/RISK/GSK3β signaling.

机构信息

Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.

出版信息

Int J Cardiol. 2013 Oct 9;168(4):3671-8. doi: 10.1016/j.ijcard.2013.06.037. Epub 2013 Jul 12.

DOI:10.1016/j.ijcard.2013.06.037

PMID:23856444

Abstract

BACKGROUND

Recent studies have demonstrated that volatile anesthetic preconditioning confers myocardial protection against ischemia-reperfusion (IR) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been shown to be impaired in hypercholesterolemia, we investigate whether anesthetic-induced cardiac protection was maintained in hypercholesterolemic rats.

METHODS

Normocholesteolemic or hypercholesterolemic rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Animals received 2.4% sevoflurane during three 5 min periods with and without PI3K antagonist wortmannin (10 μg/kg, Wort) or the ERK inhibitor PD 98059 (1 mg/kg, PD). The infarct size, apoptosis, p-Akt, p-ERK1/2, p-GSK3β were determined.

RESULTS

Two hundred and six rats were analyzed in the study. In the healthy rats, sevoflurane significantly reduced infarct size by 42%, a phenomenon completely reversed by wortmannin and PD98059 and increased the phosphorylation of Akt, ERK1/2 and their downstream target of GSK3β. In the hypercholesterolemic rats, sevoflurane failed to reduce infarct size and increase the phosphorylated Akt, ERK1/2 and GSK3β. In contrast, GSK inhibitor SB216763 conferred cardioprotection against IR injury in healthy and hypercholesterolemic hearts.

CONCLUSIONS

Hyperchoesterolemia abrogated sevoflurane-induced cardioprotection against IR injury by alteration of upstream signaling of GSK3β and acute GSK inhibition may provide a novel therapeutic strategy to protect hypercholesterolemic hearts against IR injury.

摘要

背景

最近的研究表明，挥发性麻醉预处理通过激活再灌注损伤挽救激酶（RISK）通路对缺血再灌注（IR）损伤产生心肌保护作用。由于 RISK 在高胆固醇血症中已经显示受损，我们研究了麻醉诱导的心脏保护是否在高胆固醇血症大鼠中得以维持。

方法

正常胆固醇血症或高胆固醇血症大鼠心脏经历 30 分钟缺血和 2 小时再灌注。动物在三个 5 分钟期间接受 2.4%七氟醚，同时给予或不给予 PI3K 拮抗剂渥曼青霉素（10μg/kg，Wort）或 ERK 抑制剂 PD 98059（1mg/kg，PD）。测定梗死面积、凋亡、p-Akt、p-ERK1/2、p-GSK3β。

结果

本研究共分析了 206 只大鼠。在健康大鼠中，七氟醚显著减少 42%的梗死面积，这一现象完全被渥曼青霉素和 PD98059 以及 Akt、ERK1/2 及其下游靶标 GSK3β的磷酸化逆转。在高胆固醇血症大鼠中，七氟醚未能减少梗死面积并增加磷酸化 Akt、ERK1/2 和 GSK3β。相比之下，GSK 抑制剂 SB216763 在健康和高胆固醇血症心脏中对 IR 损伤赋予了心脏保护作用。