J Cell Mol Med. 2026 May;30(10):e71187. doi: 10.1111/jcmm.71187.
ABSTRACT
Vascular endothelial cells maintain vascular homeostasis by releasing mediators with vasoconstrictive and vasorelaxant effects. Prostanoids are bioactive substances synthesised by cyclooxygenase2 (COX2); they preserve vascular function and can increase the risk of cardiovascular disease (CVD) associated with ageing. Age-related reductions in nicotinamide adenine dinucleotide (NAD+) have been implicated in CVD pathogenesis. However, the relationship between intracellular NAD+ levels and prostanoid production in vascular endothelial cells is unclear. Herein, reduced intracellular NAD+ levels upregulated COX2 protein expression by activating the p38 mitogen-activated protein kinase (MAPK) signalling pathway, increasing the production of prostaglandin F (PGF) and thromboxane B (TXB) in human umbilical vein endothelial cells (HUVECs). Treatment with the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, FK866, decreased intracellular NAD+ levels, induced a cellular senescence-like phenotype characterised by the suppression of cell proliferation without cell death and promoted PGF and TXB production in HUVECs. FK866 treatment increased phosphorylated p38 and COX2 protein levels, whereas treatment with the p38 inhibitor, PD169316, suppressed the FK866-induced increase in COX2 expression. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD+, following FK866 treatment restored intracellular NAD+ levels, reduced the cellular senescence-like phenotype and attenuated the production of PGF and TXB. These results suggest that intracellular NAD+ appears to regulate prostanoid production in HUVECs under conditions of acute depletion.
PMID:42159653 | DOI:10.1111/jcmm.71187