AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model

• DOI: 10.1016/j.lfs.2019.02.035
• Publication Date: 2019-02-18T06:57:45Z
• Authors: Xuyang Wang; Jinyu Pan; Hui Liu; Mingjun Zhang; Dian Liu; Lu Lu; Jingjing Tian; Ming Liu; Tao Jin; Fengshuang An
• Keywords: Male; 0303 health sciences; Diabetic Cardiomyopathies; Myocardium; Caspase 1; Interleukin-1beta; Apoptosis; Diabetes Mellitus, Experimental; Rats; 3. Good health; CARD Signaling Adaptor Proteins; DNA-Binding Proteins; Disease Models, Animal; Oxidative Stress; 03 medical and health sciences; Diabetes Mellitus, Type 2; Animals; Eosine Yellowish-(YS); Female; Myocytes, Cardiac; Gene Silencing; RNA, Small Interfering; Hematoxylin

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.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-1β, and GSDMD-N were measured by western blotting.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.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.