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Myricetin alleviates sepsis-induced endothelial hyperpermeability by inhibiting pyroptosis through the suppression of
Linjun Zhao1, Long Zheng2, Jiahui Hu3
1Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Fanhai West Road, Ouhai District, Wenzhou 325000, China; Department of Emergency, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, 261 Huansha Rd, Hangzhou City 310006, China.
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.
Insights
Myricetin (MYR) protects against sepsis-induced organ damage by reducing vascular barrier dysfunction. It inhibits endothelial pyroptosis via the PAR1/NF-κB/NLRP3 pathway, improving survival in septic models.
Area of Science:
- Biomedical Science
- Pharmacology
- Immunology
Background:
- Sepsis-induced vascular endothelial barrier dysfunction is a key factor in multiple organ dysfunction syndrome (MODS).
- The role of Myricetin (MYR), a natural flavonoid, in mitigating sepsis-related endothelial damage remains unexplored.
- Understanding MYR's mechanism is crucial for developing novel therapeutic strategies against sepsis.
Purpose of the Study:
- To investigate the protective effects of Myricetin (MYR) against vascular endothelial barrier disruption in sepsis.
- To elucidate the underlying molecular mechanisms, focusing on endothelial pyroptosis and its related signaling pathways.
- To evaluate MYR's efficacy in both in vitro and in vivo models of sepsis-induced MODS.
Main Methods:
- In vitro studies utilized lipopolysaccharide (LPS)-challenged human umbilical vein endothelial cells (HUVECs) treated with MYR or a PAR1 antagonist.
- Assays included cell viability (CCK-8), cell death (LDH, TUNEL), endothelial permeability (FITC-dextran flux), and western blotting for pyroptosis markers.
- In vivo studies employed a cecal ligation and puncture (CLP) model in mice to assess vascular leakage, organ injury, and survival.
Main Results:
- MYR significantly attenuated LPS-induced hyperpermeability and cell injury in HUVECs.
- MYR suppressed protease-activated receptor 1 (PAR1) expression, NF-κB phosphorylation, and NLRP3 inflammasome activation in vitro and in vivo.
- In septic mice, MYR reduced vascular leakage, preserved endothelial integrity (CD31), alleviated organ damage, and improved survival.
Conclusions:
- Myricetin (MYR) demonstrates significant protective effects against sepsis-induced vascular endothelial barrier disruption and multiple organ dysfunction syndrome (MODS).
- MYR exerts its protective action by inhibiting PAR1-associated NF-κB/NLRP3-mediated endothelial pyroptosis.
- These findings highlight MYR as a potential therapeutic agent for managing sepsis complications.