AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model
AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model
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DOI：
10.1016/j.lfs.2019.02.035
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发表时间：
2019-03-15
期刊：
影响因子：
6.1
通讯作者：
An, Fengshuang
中科院分区：
文献类型：
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作者：
Wang, Xuyang;Pan, Jinyu;An, Fengshuang
目的：黑色素瘤 2 中不存在 (AIM2) 是一种胞质 DNA 传感器，它在炎症小体形成中发挥重要作用，并参与多种细胞功能，包括细胞焦亡、纤维化和组织损伤。本研究旨在探讨AIM2是否在糖尿病心肌病（DCM）中发挥作用，并探讨其潜在的分子机制。主要方法：将Sprague-Dawley大鼠随机分为4组：对照组、糖尿病（DM）组、DM+shAIM2组和DM+shNC组。测量大鼠的心功能。进行苏木精和伊红染色、马森染色、窦红染色和免疫组织化学。 H9c2 心肌细胞在 DMEM 中培养并用高葡萄糖处理（25 mmol/l）刺激。测量活性氧（ROS）的水平。 AIM2-siRNA用于抑制AIM2的表达。 TUNEL 测定和 EthD-III 染色用于测量细胞死亡。通过蛋白质印迹法检测 AIM2、ASC、caspase-1、IL-1 beta 和 GSDMD-N 的表达水平。 主要发现：在链脲佐菌素诱导的糖尿病大鼠模型中，与对照组相比，心脏组织中 AIM2 的表达显着增加。此外，糖尿病大鼠表现出严重的左心功能障碍，包括代谢紊乱、心脏纤维化和心肌细胞死亡。 AIM2 基因沉默可缓解代谢紊乱和心室重塑引起的心脏功能障碍。在体外，用 HG 处理 H9C2 成肌细胞显着增加 AIM2，而抑制 ROS 则降低 AIM2 水平。 AIM2-siRNA 减轻了 H9c2 心肌细胞中 GSDMD-N 相关的细胞焦亡。意义：我们的结果表明，AIM2 通过 GSDMD 途径在 HG 诱导的 ROS 介导的糖尿病心肌病的细胞死亡和纤维化中发挥重要作用。
Aims: Absent in melanoma 2 (AIM2) is a cytosolic DNA sensor which plays an important role in inflammasome formation and is involved in various cellular functions including pyroptosis, fibrosis, and tissue injury. Our study aimed to investigate whether AIM2 plays a role in diabetic cardiomyopathy (DCM) and to explore its potential molecular mechanism.Main methods: Sprague-Dawley rats were randomly divided into 4 groups: Control, Diabetes Mellitus (DM), DM+ shAIM2, and DM+ shNC. The cardiac function of rats was measured. Hematoxylin and eosin staining, Masson's staining, sinus red staining, and immunohistochemistry were performed. H9c2 cardiomyocytes were cultured in DMEM and stimulated with high-glucose treatment (25 mmol/l). The level of reactive oxygen species (ROS) was measured. AIM2-siRNA were used to inhibit the expression of AIM2. TUNEL assay and EthD-III staining were used to measure cell death. The expression levels of AIM2, ASC, caspase-1, IL-1 beta, and GSDMD-N were measured by western blotting.Key findings: In the streptozotocin-induced diabetic rat model, AIM2 expression was significantly increased in heart tissue compared with the control. Also, diabetic rats exhibited severe left ventricular dysfunction including metabolic disorder, cardiac fibrosis, and cardiomyocyte death. Gene silencing of AIM2 alleviated cardiac dysfunction which resulted from metabolic disorder and ventricular remodelling. In vitro, treatment of H9C2 cardiomyoblasts with HG significantly increased AIM2, while ROS inhibition reduced the level of AIM2. AIM2- siRNA alleviated GSDMD-N-related pyroptosis in H9c2 cardiomyoblasts.Significance: Our results indicate that AIM2 plays an important role in cell death and fibrosis in HG-induced, ROS-mediated diabetic cardiomyopathy via the GSDMD pathway.