Circ Res. 2026 Feb 25. doi: 10.1161/CIRCRESAHA.125.327592. Online ahead of print.
ABSTRACT
BACKGROUND: Atherosclerosis occurs preferentially in regions of disturbed fluid shear stress (FSS), whereas physiological laminar FSS protects against disease by suppressing endothelial inflammation. Proinflammatory versus anti-inflammatory programs are associated with glycolysis versus oxidative phosphorylation, respectively, but mechanisms are poorly understood. The TF (transcription factor) FOXO1 (forkhead box protein O1) is known to regulate endothelial metabolism and angiogenesis, but little is known about its role in endothelial inflammation.
METHODS: Endothelial cells were treated with cytokines or subjected to defined flow patterns in vitro using a parallel plate flow chamber. Immunofluorescence, RNA sequencing, and biochemical assays assessed FOXO1 localization, gene expression, and posttranslational modifications. In vivo experiments used FOXO1-floxed mice crossed with Bmx-CreERT2 for artery endothelial cell-specific FOXO1 knockout. Hyperlipidemia was induced via injection of PCSK9 (proprotein convertase subtilisin/kexin type 9) adeno-associated virus and high-cholesterol/high-fat diet to assess atherosclerosis.
RESULTS: Oscillatory FSS and inflammatory cytokines induced whereas physiological FSS inhibited FOXO1 nuclear translocation. Depleting FOXO1 in endothelial cells upregulated the protective flow-responsive TFs KLF (Krüppel-like factor) 2/4 and reduced oscillatory FSS-induced inflammatory genes. Inhibition of FOXO1 nuclear translocation by physiological FSS is mediated via a KLF2-CDK2 (cell cycle-dependent kinase 2) pathway, with the latter phosphorylating FOXO1 at S249. Artery endothelial cell-specific deletion of FOXO1 significantly reduced atherosclerotic plaques in hyperlipidemic mice. Inhibition of glycolysis blocked oscillatory shear stress-induced FOXO1 nucleus translocation, while treatment with lactate promoted FOXO1 nuclear localization. These effects required lactyltransferase AARS1 (alanyl-tRNA synthetase 1) and correlated with FOXO1 lactylation.
CONCLUSIONS: These findings identify FOXO1 as a key mediator linking atheroprone flow and endothelial inflammatory gene expression via lactate-driven lactylation and nuclear translocation, promoting atherosclerosis. Conversely, physiological FSS suppresses FOXO1 via KLF2-CDK2 signaling. These complementary pathways suggest potential new therapeutic targets for treating atherosclerotic cardiovascular disease.
PMID:41738126 | DOI:10.1161/CIRCRESAHA.125.327592