NLRP3-induced endoplasmic reticulum stress, oxidative stress, and inflammatory response in the progression of diabetic cardiomyopathy

Abstract Objective This study aimed to investigate the mechanisms underlying the interaction between the inflammasome nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), endoplasmic reticulum stress (ERS), oxidative stress, and inflammatory response in promoting the progression of diabetic cardiomyopathy (DCM). Methods To evaluate the role of NLRP3 in DCM pathogenesis, animals were randomly divided into three groups: control (CTL), diabetic (DM), and diabetic + glibenclamide (GLB). The diabetic model was induced by intraperitoneal injection of streptozotocin (1.25 mg/kg), and the GLB group received glibenclamide (1.25 mg/kg) for 8 weeks post-diabetes induction. Various parameters, including life signs, echocardiography, epicardial activation mapping, in vivo electrophysiological examination, protein blotting, enzyme immunoassay, histological examination, and fluorescence staining, were analyzed to assess myocardial structural and electrical remodeling in DCM. Results In the DM group, significant increases were observed in the heart-to-body weight ratio, atrial weight ratio, left atrial diameter, and septal thickness compared to the CTL group. Pathological analysis revealed disordered myocardial cell arrangement, pronounced inflammatory cell infiltration, and elevated interstitial fibrosis in the DM group. Fluorescence staining indicated higher levels of reactive oxygen species (ROS) in the DM group. Electrophysiological studies showed reduced epicardial conduction velocity, increased absolute heterogeneity and heterogeneity index, and a higher incidence of atrial fibrillation in the DM group. Western blot analysis demonstrated upregulated expression of ERS-related proteins (e.g., calcium-dependent protein kinase II, inositol-requiring protein 1 alpha), oxidative stress-related proteins (e.g., NADPH oxidase NOX2, NOX4), and inflammation-related proteins (e.g., NLRP3, caspase-1, galectin-3, transforming growth factor-β1) in the DM group. Additionally, caspase-1 activity and serum levels of interleukin (IL)-1β and IL-18 were significantly elevated in the DM group. These pathological changes were ameliorated in the GLB group compared to the DM group. Conclusions High glucose levels induce ERS in cardiomyocytes via NLRP3 activation, promoting oxidative stress and upregulating inflammatory responses, ultimately accelerating DCM progression through both structural and electrical remodeling.