Ning Xia Medical University, Yin Chuan, China.
Department of Anesthesiology, Tumor Hospital, General Hospital of Ning Xia Medical University, Yin Chuan, China.
Environ Toxicol Pharmacol. 2016 Mar;42:85-91. doi: 10.1016/j.etap.2016.01.004. Epub 2016 Jan 9.
Some findings have suggested that the rescue of bupivacaine (BPV)-induced cardiotoxicity by lipid emulsion (LE) is associated with inhibition of mitochondrial permeability transition pore (mPTP). However, the mechanism of this rescue action is not clearly known. In this study, the roles of phosphoinositide 3-kinase (PI3K)/Akt and glycogen synthase kinase-3β (GSK-3β) in the molecular mechanism of LE-induced protection and its relationship with mPTP were explored. h9c2 cardiomyocytes were randomly divided into several groups: control, BPV, LE, BPV+LE. To study the effect of LE on mPTP, atractyloside (Atr, 20 μM, mPTP opener) and cyclosporine A (CsA, 10 μM, mPTP blocker) were used. To unravel whether LE protects heart through the PI3K/Akt/GSK-3β signaling pathway, cells were treated with LY294002 (LY, 30 μM, PI3K blocker) or TWS119 (TWS 10 μM, GSK-3β blocker). Later mitochondrial respiratory chain complexes, apoptosis, opening of mPTP and phosphorylation levels of Akt/GSK-3β were measured. LE significantly improved the mitochondrial functions in h9c2 cardiomyocytes. LE reversed the BPV-induced apoptosis and the opening of mPTP. The effect of LE was not only enhanced by CsA and TWS, but also abolished by Atr and LY. LE also increased the phosphorylation levels of Akt and GSK-3β. These results suggested that LE can reverse the apoptosis in cardiomyocytes by BPV and a mechanism of its action is inhibition of mPTP opening through the PI3K/Akt/GSK-3β signaling pathway.
一些研究结果表明，脂肪乳（LE）对布比卡因（BPV）诱导的心脏毒性的抢救作用与抑制线粒体通透性转换孔（mPTP）有关。然而，这种抢救作用的机制尚不清楚。在这项研究中，探讨了磷酯酰肌醇 3-激酶（PI3K）/Akt 和糖原合成酶激酶-3β（GSK-3β）在 LE 诱导的保护的分子机制中的作用及其与 mPTP 的关系。 h9c2 心肌细胞被随机分为几组：对照组、BPV 组、LE 组、BPV+LE 组。为了研究 LE 对 mPTP 的影响，使用了 atractyloside（Atr，20μM，mPTP 开放剂）和环孢菌素 A（CsA，10μM，mPTP 阻断剂）。为了阐明 LE 是否通过 PI3K/Akt/GSK-3β 信号通路来保护心脏，用 LY294002（LY，30μM，PI3K 阻断剂）或 TWS119（TWS，10μM，GSK-3β 阻断剂）处理细胞。然后测量线粒体呼吸链复合物、细胞凋亡、mPTP 的开放以及 Akt/GSK-3β 的磷酸化水平。 LE 显著改善了 h9c2 心肌细胞中的线粒体功能。 LE 逆转了 BPV 诱导的细胞凋亡和 mPTP 的开放。 LE 的作用不仅被 CsA 和 TWS 增强，而且被 Atr 和 LY 所消除。 LE 还增加了 Akt 和 GSK-3β 的磷酸化水平。这些结果表明，LE 可以通过 PI3K/Akt/GSK-3β 信号通路抑制 mPTP 的开放来逆转心肌细胞中的细胞凋亡。
