Empagliflozin attenuates pyroptosis by regulating thioredoxin-NLRP3 inflammasome axis in a high fat cholesterol diet/streptozotocin model of atherosclerosis

Objectives Oxidative stress (OS), inflammation, and pyroptosis are hallmarks of atherosclerosis pathogenesis. Thioredoxin-interacting protein (TXNIP) crosslinks them through activating nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome pathway. The current work addresses the potentials of empagliflozin (EMPA) on OS markers, thioredoxin (TRX), and TXNIP, downstream mediators of NLRP3 inflammasome and the executioner of pyroptosis; gasdermin D (GSDMD) in a model of atherosclerosis. Methods Atherosclerosis was induced by high fat cholesterol diet (HFCD) and streptozotocin (STZ) in male Wistar rats. Five groups were allocated: Control group, HFCD-STZ group, and three orally EMPA treated groups with HFCD-STZ in doses (2.5, 5, and 10 mg/kg/d for 4 weeks). To access the underlying mechanism of EMPA on atherosclerosis, serum glycated haemoglobin, lipid profile, inflammatory cytokines, and aortic OS markers were evaluated. Polymerase chain reaction analysis of NLRP3 inflammasome components, TRX, TXNIP, GSDMD, and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions were performed. Histopathological studies further confirmed EMPA’s effects on atherosclerosis. Key findings EMPA ameliorates metabolic and histopathological alterations, inflammation, OS, TRRX/TXNIP reversal, VCAM-1, activation of NLRP3 inflammasome, and pyroptosis axis. Conclusions EMPA displayed antioxidant and anti-inflammatory effects through attenuating the OS/TXNIP/NLRP3/GSDMD axis in an experimental model of atherosclerosis.