Am J Physiol Heart Circ Physiol. 2026 Jun 12. doi: 10.1152/ajpheart.00974.2025. Online ahead of print.
ABSTRACT
Inflammation and metabolism reprogramming are hallmarks of calcific aortic valve disease (CAVD). Recent studies link hyperglycolysis, inflammation, and calcification in valve interstitial cells (VICs). The metabolism of valve endothelial cells (VECs) has received less attention despite the fact that both resident valve cells are exposed to alike inflammatory clues involved in the biosynthesis of pathologically relevant glycoproteins at early stages of CAVD. Given this, we investigated the outcomes of glucose metabolism rewiring on glycoprotein maturation and monocyte adhesion in human resident valve cells. Real-time metabolic analysis revealed that basal VECs are more glycolytic than VICs. Also, VECs and VICs exposed to inflammatory stimuli exhibited a distinct rewiring, with VECs shifting to a more energetic metabolism, despite a similar upregulation of glycolytic genes. Blunting glucose metabolism in VICs and VECs inhibited inflammatory routes canonically associated with glycolysis, and the expression of proteins associated to the inflammatory response like interleukin-6 and cyclooxygenase-2. Moreover, the expression and post-translational modifications of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 showed glucose-dependency and sex-related differences. The ensuing process of monocyte-valve cell adhesion was glucose-dependent. Notably, inhibiting the branch route of hexosamine biosynthesis with DON and N-glycosylation by tunicamycin disrupted adhesion molecule maturation. Under shear stress conditions, 2-DG impaired monocyte rolling and adhesion to VECs monolayers, while DON reduced rolling. In conclusion, glycolysis and its side-branch route of hexosamine biosynthesis are necessary for nutrient-driven post-translational modifications of inflammatory proteins in inflamed valve cells and key steps of monocyte recruitment, a crucial process in early-stages of CAVD.
PMID:42284201 | DOI:10.1152/ajpheart.00974.2025