The ER stress-mediated mitochondrial apoptotic pathway and MAPKs modulate tachypacing-induced apoptosis in HL-1 atrial myocytes.
The ER stress-mediated mitochondrial apoptotic pathway and MAPKs modulate tachypacing-induced apoptosis in HL-1 atrial myocytes.
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ER 应激介导的线粒体凋亡途径和 MAPK 调节 HL-1 心房肌细胞中快速起搏诱导的细胞凋亡
DOI：
10.1371/journal.pone.0117567
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Chen M
中科院分区：
文献类型：
--
作者：
Shi J;Jiang Q;Ding X;Xu W;Wang DW;Chen M
背景和对象细胞凋亡是心房颤动（AF）发生、进展和复发的一个促成因素，房颤是一种伴有中风和心力衰竭的危及生命的疾病。然而，细胞凋亡的调控级联是复杂的且仍未明确，特别是在房颤的情况下。本研究的目的是探讨内质网 (ER) 应激、线粒体凋亡途径 (MAP)、丝裂原激活蛋白激酶 (MAPK) 的作用及其在快速起搏诱导的细胞凋亡中的相互作用。方法和结果 HL-1 细胞在起搏存在下培养 24 小时以模拟房性心动过速重塑。结果显示，通过细胞计数试剂盒 8 测量，快速起搏降低了细胞活力，通过 JC-1 染色检测到线粒体膜电位消散，通过 Hoechst 染色和膜联蛋白 V/碘化丙啶染色检测，导致约 50% 的细胞凋亡。此外，蛋白质印迹证实，参与 ER 应激的蛋白质、MAP 和 MAPK 普遍上调或通过磷酸化激活；在起搏之前用特定抑制剂反向沉默 ER 应激、caspase-3（MAP 的最终执行者）和 MAPK，可部分减轻细胞凋亡。应用内质网应激抑制剂进一步研究线粒体和MAPKs对内质网应激的反应，结果表明，内质网应激的抑制全面但不完全地减弱了快速起搏引起的MAP和MAPKs的激活，但MAPKs的一个分支ERK1/2除外。结论 我们的研究表明，快速起搏诱导的细胞凋亡受到 ER 应激介导的 MAP 和 MAPK 的调节。因此，上述三个成分都是 AF 患者有希望的抗凋亡靶点，而 ER 应激由于其综合作用似乎发挥着主导作用。
Background and Object Cell apoptosis is a contributing factor in the initiation, progression and relapse of atrial fibrillation (AF), a life-threatening illness accompanied with stroke and heart failure. However, the regulatory cascade of apoptosis is intricate and remains unidentified, especially in the setting of AF. The aim of this study was to explore the roles of endoplasmic reticulum (ER) stress, mitochondrial apoptotic pathway (MAP), mitogen-activated protein kinases (MAPKs), and their cross-talking in tachypacing-induced apoptosis. Methods and Results HL-1 cells were cultured in the presence of tachypacing for 24 h to simulate atrial tachycardia remodeling. Results showed that tachypacing reduced cell viability measured by the cell counting kit-8, dissipated mitochondrial membrane potential detected by JC-1 staining and resulted in approximately 50% apoptosis examined by Hoechst staining and annexin V/propidium iodide staining. In addition, the proteins involved in ER stress, MAP and MAPKs were universally up-regulated or activated via phosphorylation, as confirmed by western blotting; and reversely silencing of ER stress, caspase-3 (the ultimate executor of MAP) and MAPKs with specific inhibitors prior to pacing partially alleviated apoptosis. An inhibitor of ER stress was applied to further investigate the responses of mitochondria and MAPKs to ER stress, and results indicated that suppression of ER stress comprehensively but incompletely attenuated the activation of MAP and MAPKs aroused by tachypacing, with the exception of ERK1/2, one branch of MAPKs. Conclusions Our study suggested tachypacing-induced apoptosis is regulated by ER stress-mediated MAP and MAPKs. Thus, the above three components are all promising anti-apoptotic targets in AF patients and ER stress appears to play a dominant role due to its comprehensive effects.
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