FOXA1 exacerbates LPS-induced vascular endothelial cell injury in sepsis by suppressing the transcription of NRP2.

Endothelial dysfunction plays a critical role in the pathogenesis of sepsis. This study aims to explore the effect and mechanism of forkhead box A1 (FOXA1) on vascular endothelial cell injury in sepsis. Human umbilical vein endothelial cells (HUVECs) were stimulated by lipopolysaccharide (LPS). Lactate dehydrogenase (LDH) release, cell viability, apoptosis, and inflammatory factors including IL-1β, TNF-α, and IL-6 were measured using LDH kits, CCK-8 assay, flow cytometry, and ELISA respectively. RT-qPCR or Western blot determined the expression of FOXA1 or neuropilin-2 (NRP2) in cells. The binding between FOXA1 and NRP2 was confirmed using ChIP and dual-luciferase assays. Functional rescue experiments were performed to verify the effect of FOXA1 siRNA or NRP2 siRNA on cell injury. LPS treatment induced endothelial cell injury in a concentration-dependent manner. FOXA1 expression was elevated after LPS treatment. FOXA1 silencing reduced LDH release, enhanced cell viability, suppressed apoptosis, and declined inflammation factors. Mechanistically, FOXA1 bound to the NRP2 promoter to suppress the transcription of NRP2. Functional rescue experiments revealed that knockdown of NRP2 offset the protective effect of knockdown of FOXA1 on cell injury. In conclusion, FOXA1 exacerbates LPS-insulted endothelial cell injury in sepsis by repressing the transcription of NRP2.