Adiponectin protects HL-1 cardiomyocytes against rotenone-induced cytotoxicity through AMPK activation
Adiponectin protects HL-1 cardiomyocytes against rotenone-induced cytotoxicity through AMPK activation
复制标题
脂联素通过 AMPK 激活保护 HL-1 心肌细胞免受鱼藤酮诱导的细胞毒性
DOI：
10.1016/j.toxlet.2020.10.010
复制
发表时间：
2020-12-15
影响因子：
3.5
通讯作者：
Liu, Qiming
中科院分区：
文献类型：
--
作者：
Li, Biao;Zhang, Baojian;Liu, Qiming
线粒体功能障碍或内质网应激与心血管疾病的发病机制之间的关系已有很好的文献记载，但它们在心血管疾病中的相互作用尚不清楚。脂联素(APN)已被报道成为一种潜在的心肌保护分子，但APN是否以及如何调节线粒体功能障碍和内质网应激尚不清楚。本研究使用鱼藤酮处理的HL-1心房肌细胞作为线粒体功能障碍的体外模型，研究线粒体功能障碍与内质网应激之间的可能相互作用，并探讨APN对鱼藤酮诱导的细胞毒性的影响及其机制。研究发现，鱼藤酮处理显著激活了内质网应激PRK样内质网激酶(PERK)依赖的途径，降低了自噬通量和APN的表达，并呈剂量依赖关系。PERK活性抑制剂GSK2606414可减弱鱼藤酮诱导的APN表达下降。反过来，外源性APN可抑制鱼藤酮诱导的内质网应激，通过激活AMPK激活自噬，保护HL-1细胞免受凋亡，提高鱼藤酮处理后的细胞存活率。综上所述，鱼藤酮可诱导HL-1细胞产生明显的心肌细胞毒作用和内质网应激，抑制自噬，减少APN的表达。APN通过激活AMPK抑制内质网应激，激活自噬，从而减轻鱼藤酮诱导的HL-1细胞凋亡。(C)2020爱思唯尔B.V.保留所有权利。
The relationship between mitochondrial dysfunction or ER stress with pathogenesis of cardiovascular disease is well documented, but the crosstalk between them in cardiovascular diseases is not clear. Adiponectin (APN) is reported to become a potential cardioprotective molecule, but whether and how APN regulates mitochondrial dysfunction and ER stress is not clear. In this study, we used rotenone-treated HL-1 atrial cardiomyocytes as an in vitro model of mitochondrial dysfunction to investigate the possible interactions between mitochondrial dysfunction and ER stress and explore the effects of APN on rotenone-induced cytotoxicity and the underlying mechanisms. It found that rotenone treatment significantly activated the ER stress PRK-like endoplasmic reticulum kinase (PERK)-dependent pathway, decreased autophagic flux and APN expression in a dose-dependent manner. Pretreatment of GSK2606414, an inhibitor of PERK kinase activity, attenuated the rotenone-induced decrease of APN expression. In return exogenous APN pretreatment inhibited rotenone-induced ER stress and activated autophagy via AMP-activated protein kinase (AMPK) activation and protected HL-1 cells against apoptosis and enhanced the viability after rotenone treatment. In conclusion, rotenone treatment induced significant cardiomyocyte cytotoxicity and ER stress, suppressed autophagy, and decreased APN expression in HL-1 cells. APN in return inhibited ER stress and activated autophagy through AMPK activation, thus alleviating rotenone induced HL-1 apoptosis. (C) 2020 Elsevier B.V. All rights reserved.