Myricetin alleviates sepsis-induced endothelial hyperpermeability by inhibiting pyroptosis through the suppression of PAR1.

Abstract

Dysfunction of the vascular endothelial barrier is a pivotal event in the pathogenesis of sepsis-induced multiple organ dysfunction syndrome (MODS). Myricetin (MYR), a naturally occurring flavonoid compound with diverse biological activities, has not been previously reported for its role and mechanism in septic vascular endothelial barrier disruption. Therefore, this study aimed to elucidate the protective effects and underlying mechanisms of MYR against vascular endothelial barrier disruption and MODS in sepsis. In vitro, lipopolysaccharide (LPS)-challenged human umbilical vein endothelial cells (HUVECs) were treated with MYR or the protease-activated receptor 1 (PAR1) antagonist SCH79797. Cell viability, cell death, endothelial permeability and pyroptosis-related signaling were evaluated using CCK-8, LDH release, TUNEL, FITC-dextran flux, immunofluorescence and western blotting assays. A cecal ligation and puncture (CLP)-induced murine sepsis model was established to assess vascular leakage, histopathological injury and pulmonary pyroptotic signaling in vivo. MYR attenuated LPS-induced endothelial hyperpermeability and reduced cell injury in HUVECs. In both LPS-stimulated HUVECs and lung tissues from CLP-induced septic mice, MYR decreased PAR1 expression, inhibited NF-κB p65 phosphorylation, and suppressed NLRP3 inflammasome activation, as indicated by reduced levels of NLRP3, ASC, pro-caspase-1, IL-1β, IL-18, cleaved-caspase-1, GSDMD and NT-GSDMD. Consistently, SCH79797 produced similar inhibitory effects on NF-κB/NLRP3-mediated pyroptosis. In septic mice, MYR reduced vascular leakage, preserved CD31 expression, alleviated multiorgan injury and improved survival. These findings suggest that MYR alleviates septic endothelial barrier disruption and MODS, at least in part, by suppressing PAR1-associated NF-κB/NLRP3-mediated endothelial pyroptosis.