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Effects of ENO1 knockdown and LPS+Lactate stimulation on EA.HY926 cells

ABSTRACT: Elevated lactate was associated with vascular endothelial cells (ECs) dysfunction in sepsis. However, the underlying mechanisms remain to be defined. In this study, we found that elevated lactate in sepsis promotes lactylation of enolase 1 (ENO1) at K71 site through the action of lactyltransferase P300. The lactylation at ENO1 K71 site reduces the binding of TRIM21(an E3 ubiquitin ligase) mRNA to ENO1 (an RNA-binding protein), resulting in enhanced TRIM21 mRNA stability and expression. Elevated TRIM21 can bind to VE-Cadherin and exert its E3 ubiquitin ligase function, causing the ubiquitination and degradation of VE-Cadherin, which disrupts endothelial adhesions junctions (AJs) and increases endothelial permeability. Targeting lactylation of ENO1 K71 via a specific peptide alleviated endothelial injury and enhanced survival rates among septic mice. These findings suggest that lactyaltion of ENO1 plays a pivotal role in vascular endothelial dysfuncyion during sepsis, while inhibiting lactylation may offer a novel strategy for sepsis treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281679 | GEO | 2026/01/21

REPOSITORIES: GEO

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Project description:Rationale: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumours, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular inter-endothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, vascular endothelial (VE)-cadherin (VEC), upregulate genes with key roles in endothelial differentiation and stability. Objective: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. Methods and Results: We compared a VEC-null cell line with the same line reconstituted with VEC wild type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, Vascular Endothelial-Protein Tyrosine Phosphatase (VE-PTP) and von Willebrand factor (vWf). Mechanistically VEC exerts this effect by inhibiting Polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 and β-catenin, which contribute to Polycomb repressive complex-2 (PRC2) binding to promoter regions of claudin-5, VE-PTP and vWf. VE-cadherin/β-catenin complex also sequesters a core subunit of PRC2 (Ezh2) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VE-cadherin association increases Ezh2 recruitment to claudin-5, VE-PTP and vWf promoters, causing gene downregulation. RNAseq comparison of VEC-null and VEC-positive cells suggested a more general role of VE-cadherin in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of Claudin-5 and VE-PTP. Conclusions: These data extend the knowledge of Polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the Polycomb-mediated repression system. Keywords: Polycomb, endothelial cells, VE-cadherin, vessel maturation, vascular biology, vascular permeability, cell signalling, epigenetics, gene regulation. Downloaded from http://circres.ahajour Conclusions: These data extend the knowledge of Polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the Polycomb-mediated repression system

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Effects of ENO1 knockdown and LPS+Lactate stimulation on EA.HY926 cells

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