Notoginsenoside‐Fa mitigates vascular endothelial permeability via targeting SUGT1 to stabilize NLRP3 in a resting state

BACKGROUND AND PURPOSE: Notoginsenoside-Fa (Noto-Fa) is an emerging active compound derived from notoginseng with promise in treating cardiovascular diseases. The development of cardiovascular diseases is intricately linked to the damage of vascular endothelium and it is widely acknowledged that numerous chronic inflammation pathways, especially the NLRP3 inflammasome pathway. However, the therapeutic effects and the underlying mechanisms of Noto-Fa on vascular endothelial dysfunction is still unclear. EXPERIMENTAL APPROACH: Luminex xMAP technology was used to measure the levels of inflammatory cytokines in mouse serum. Transmission electron microscope (TEM), immunofluorescence, trans endothelial electric resistance (TEER) and FITC-dextran flux was used to detect vascular endothelial function. Western blotting was used to determine the expression of NLRP3 inflammasome-related proteins. Endothelial adhesion and permeability assessed by mouse endothelial cells (MECs) and THP-1 cells co-culture in vitro. Immunoprecipitation was used to examine the effect of Noto-Fa on the association of SUGT1, HSP90 and NLRP3 proteins. CETSA, molecular docking, SPR and Dot blot were used to determine the interaction of Noto-Fa with SUGT1. KEY RESULTS: Noto-Fa administration dose-dependently inhibited vascular endothelial damage evidenced by increased tight junction proteins and reduced permeability. Furthermore, the activation of NLRP3 inflammasome were suppressed by Noto-Fa and low-dose Noto-Fa did not alter NLRP3 levels but eventually blocked inflammasome activation. Finally, we found that Noto-Fa could stabilize the NLRP3/ HSP90 complex via its potential to target SUGT1, keeping NLRP3 in an inactive state. CONCLUSION AND IMPLICATIONS: These results demonstrate that Noto-Fa possesses therapeutic potential in inhibiting endothelial dysfunction by regulating the SUGT1/ HSP90/ NLRP3 pathway.