miR-590-3pInhibits Pyroptosis in Diabetic Retinopathy by TargetingNLRP1and Inactivating the NOX4 Signaling Pathway

Abstract

PURPOSE. To elucidate the mechanism whereby miR-590-3p regulates pyroptosis in diabetic retinopathy (DR). METHODS. Human retinal microvascular endothelial cells (HRMECs) incubated with high glucose (HG) were used to establish cell models, and the expression levels of miR-590-3p, caspase-1, IL-1b, NLRP1, NOX4, TXNIP, NLRP3, and ROS were determined. Additionally, miR-590-3p was altered using a mimic or an inhibitor, and siRNAs targeting NLRP1 and NOX4 were applied to explore the regulatory mechanism of miR-590-3p in DR. The relationships between miR-590-3p and NLRP1/NOX4 also were investigated using a luciferase reporter assay. Furthermore, vitreous tissue samples were collected to confirm pyroptosis in clinical DR. RESULTS. Downregulated miR-590-3p and upregulated NLRP1/NOX4 levels were observed in a cell culture model of DR. Inhibiting miR-590-3p upregulated NLRP1, the NOX4/ROS/TXNIP/ NLRP3 pathway, and caspase-1. NLRP1 and NOX4 were confirmed as direct target genes of miR-590-3p. The overexpression of miR-590-3p or knockdown of NLRP1 and NOX4 increased cell activity and suppressed pyroptosis. Intriguingly, the upregulation of IL-1b induced the downregulation of miR-590-3p by lowering the DNA promoter activity of pri-miR-590. CONCLUSIONS. HG induced pyroptosis in a cell culture model of DR, and the downregulation of miR-590-3p promoted pyroptotic death by targeting NLRP1 and activating the NOX4/ROS/ TXNIP/NLRP3 pathway via an IL-1b-mediated positive feedback loop.

miRNA-141 Induced Pyroptosis in Intervertebral Disk Degeneration by Targeting ROS Generation and Activating TXNIP/NLRP3 Signaling in Nucleus Pulpous Cells

“…Also, miRNA-141 increased ROS generation in NPCs and its effect was synergistic with that of acidity. ROS activates TXNIP/NLRPS signaling, which plays an important role in pyroptosis (Chavarria-Smith and Vance, 2015;Gu et al, 2019). In this study, miRNA-141 upregulated the expression of TXNIP and NLRP3 in a ROS-dependent manner.…”

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

“…These inflammasomes recruit adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to activate caspase1 [41]. Caspase1 can cleave GSDMD to generate the N-terminal domain of GSDMD (GSDMD-N), which permeabilizes the plasma membrane, undergoing pyroptosis [18,[42][43][44]. GSDMD has been widely characterized for its ability to form necrotic pores in the plasma membrane.…”

“…High glucose enhances IL-1β-mediated pyroptosis by targeting NLRP1 and activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)/ROS/TXNIP/NLRP3 pathway in a cell culture model of diabetic retinopathy (DR). Overexpressed miR-590-3p inhibits pyroptosis and it might be an effective interfering target for the prevention and treatment of DR [42]. Hydrogen peroxide causes cardiomyocytes injury and mice are ligated with the left anterior descending coronary artery to induce myocardial infarction (MI).…”

The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress

“…miR-106a was revealed as downexpressed in the pathogenesis of diabetic peripheral neuropathy, thus contributing to 12/15-lipoxygenase (12/15-LOX)-dependent OxS and NS [252]. miR-590-3p was downregulated in HG-affected retinal microvascular endothelial cells (HRMECs) allowing for increased expression of its target, and activation of NOX4 [253]. HG treatment in retinal endothelial cells evoked reduction of miR-145 together with increase of signaling via TLR4/NF-κB pathway, potentiation of OxS, inflammation and apoptosis.…”